Kinase inhibitors

ABSTRACT

Compounds, pharmaceutical compositions, kits and methods are provided for use with kinases that comprise a compound of the formula: 
                         
wherein R 1 , R 2 , R 3 , Q, U, V, W, X, and Y are as defined herein.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/602,902 filed Aug. 18, 2004, which is incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to compounds that may be used to inhibit kinasesas well as compositions of matter and kits comprising these compounds.The present invention also relates to methods for inhibiting kinases aswell as treatment methods using compounds according to the presentinvention.

BACKGROUND OF THE INVENTION

The invention relates to inhibitors of enzymes that catalyze phosphoryltransfer and/or that bind ATP/GTP nucleotides, compositions comprisingthe inhibitors, and methods of using the inhibitors and inhibitorcompositions. The inhibitors and compositions comprising them are usefulfor treating or modulating disease in which phosphoryl transferases,including kinases, may be involved, symptoms of such disease, or theeffect of other physiological events mediated by phosphoryltransferases, including kinases. The invention also provides for methodsof making the inhibitor compounds and methods for treating diseases inwhich one or more phosphoryl transferase, including kinase, activitiesis involved.

Phosphoryl transferases are a large family of enzymes that transferphosphorous-containing groups from one substrate to another. By theconventions set forth by the Nomenclature Committee of the InternationalUnion of Biochemistry and Molecular Biology (IUBMB) enzymes of this typehave Enzyme Commission (EC) numbers starting with 2.7.-.- (See, BairochA., The ENZYME database in Nucleic Acids Res. 28:204-305 (2000)).Kinases are a class of enzymes that function in the catalysis ofphosphoryl transfer. The protein kinases constitute the largestsubfamily of structurally related phosphoryl transferases and areresponsible for the control of a wide variety of signal transductionprocesses within the cell. (See, Hardie, G. and Hanks, S. (1995) TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.).Protein kinases are thought to have evolved from a common ancestral genedue to the conservation of their structure and catalytic function.Almost all kinases contain a similar 250-300 amino acid catalyticdomain. The protein kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, histidine, etc.). Protein kinase sequencemotifs have been identified that generally correspond to each of thesekinase families (See, for example, Hanks, S. K.; Hunter, T., FASEB J.9:576-596 (1995); Kinghton et al., Science, 253:407-414 (1991); Hiles etal., Cell 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993);Garcia-Bustos et al., EMBO J., 13:2352-2361 (1994)). Lipid kinases (e.g.PI3K) constitute a separate group of kinases with structural similarityto protein kinases.

Protein and lipid kinases regulate many different cell processesincluding, but not limited to, proliferation, growth, differentiation,metabolism, cell cycle events, apoptosis, motility, transcription,translation and other signaling processes, by adding phosphate groups totargets such as proteins or lipids. Phosphorylation events catalyzed bykinases act as molecular on/off switches that can modulate or regulatethe biological function of the target protein. Phosphorylation of targetproteins occurs in response to a variety of extracellular signals(hormones, neurotransmitters, growth and differentiation factors, etc.),cell cycle events, environmental or nutritional stresses, etc. Proteinand lipid kinases can function in signaling pathways to activate orinactivate, or modulate the activity of (either directly or indirectly)the targets. These targets may include, for example, metabolic enzymes,regulatory proteins, receptors, cytoskeletal proteins, ion channels orpumps, or transcription factors. Uncontrolled signaling due to defectivecontrol of protein phosphorylation has been implicated in a number ofdiseases and disease conditions, including, for example, inflammation,cancer, allergy/asthma, diseases and conditions of the immune system,disease and conditions of the central nervous system (CNS),cardiovascular disease, dermatology, and angiogenesis.

Initial interest in protein kinases as pharmacological targets wasstimulated by the findings that many viral oncogenes encode structurallymodified cellular protein kinases with constitutive enzyme activity.These findings pointed to the potential involvement of oncogene relatedprotein kinases in human proliferatives disorders. Subsequently,deregulated protein kinase activity, resulting from a variety of moresubtle mechanisms, has been implicated in the pathophysiology of anumber of important human disorders including, for example, cancer, CNSconditions, and immunologically related diseases. The development ofselective protein kinase inhibitors that can block the diseasepathologies and/or symptoms resulting from aberrant protein kinaseactivity has therefore generated much interest.

Cancer results from the deregulation of the normal processes thatcontrol cell division, differentiation and apoptotic cell death. Proteinkinases play a critical role in this regulatory process. A partialnon-limiting list of such kinases includes abl, Aurora-A, Aurora-B,Aurora-C, ATK, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, c-Src, CDK1, CDK2,CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Flt-1, Fps, Frk, Fyn,Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2,Ros, Tie1, Tie2, Trk, Yes and Zap70. In mammalian biology, such proteinkinases comprise mitogen activated protein kinase (MAPK) signalingpathways. MAPK signaling pathways are inappropriately activated by avariety of common disease-associated mechanisms such as mutation of rasgenes and deregulation of growth factor receptors (Magnuson et al.,Seminars in Cancer Biology 5:247-252 (1994)). Therefore the inhibitionof protein kinases is an object of the present invention.

Aurora kinases (Aurora-A, Aurora-B, Aurora-C) are serine/threonineprotein kinases that have been implicated in human cancer, such ascolon, breast and other solid tumors. Aurora-A (also sometimes referredto as AIK) is believed to be involved in protein phosphorylation eventsthat regulate the cell cycle. Specifically, Aurora-A may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, Aurora-A, Aurora-B,Aurora-C have been found to be overexpressed (See, Bischoff et al., EMBOJ., 17:3052-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646(1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).

There is a continued need to find new therapeutic agents to treat humandiseases. The protein kinases, specifically but not limited to Aurora-A,Aurora-B and Aurora-C are especially attractive targets for thediscovery of new therapeutics due to their important role in cancer,diabetes, Alzheimer's disease and other diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting kinases. The present invention also provides compositions,articles of manufacture and kits comprising these compounds.

In one embodiment, a pharmaceutical composition is provided thatcomprises a kinase inhibitor according to the present invention as anactive ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more kinaseinhibitors of this invention. These pharmaceutical compositions may beadministered or coadministered by a wide variety of routes, includingfor example, orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery (for example by catheter or stent),subcutaneously, intraadiposally, intraarticularly, or intrathecally. Thecompositions may also be administered or coadministered in slow releasedosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with kinases.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one kinase inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one kinase inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit kinases.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which kinasespossesses activity that contributes to the pathology and/or symptomologyof the disease state.

In another embodiment, a compound is administered to a subject whereinkinases activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitskinases.

In another embodiment, a method of inhibiting kinases is provided thatcomprises contacting kinases with a compound according to the presentinvention.

In another embodiment, a method of inhibiting kinases is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit kinases in vivo.

In another embodiment, a method of inhibiting kinases is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibitskinases in vivo. It is noted that the compounds of the present inventionmay be the first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of inhibiting cell proliferation isprovided that comprises contacting a cell with an effective amount of acompound according to the present invention.

In another embodiment, a method of inhibiting cell proliferation in apatient is provided that comprises administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method of treating a condition in a patientwhich is known to be mediated by kinases, or which is known to betreated by kinase inhibitors, comprising administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of disease state which is known to be mediatedby kinases, or which is known to be treated by kinase inhibitors.

In another embodiment, a method is provided for treating a disease statefor which kinases possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which kinases possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which kinases possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well know in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula” is intended to encompass the compound and all pharmaceuticallyacceptable ionized forms and solvates, all possible stereoisomers, andall possible resonance forms and tautomers unless otherwise specificallyspecified in the particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting kinases and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have kinase inhibitory activity.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with C₃₋₈ rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See“aminoalkyl”) between the carbon atoms. C_(X) alkyl and C_(X-Y) alkylare typically used where X and Y indicate the number of carbon atoms inthe chain. For example, C₁₋₆ alkyl includes alkyls that have a chain ofbetween 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl,2-propynyl, and the like). Alkyl represented along with another radical(e.g., as in arylalkyl, heteroarylalkyl) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means a bond (e.g.,(C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl, phenethyl, 1-phenylethyl,3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).

“Alkenyl” means a straight or branched, carbon chain which contains atleast one carbon-carbon double bond. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Alkynyl” means a straight or branched, carbon chain which contains atleast one carbon-carbon triple bond. Examples of alkynyl includeethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. C_(X) alkyleneand C_(X-Y) alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, C₁₋₆ alkylene includesmethylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene (—CH₂CH₂CH₂—),tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene (—CH₂CH═CHCH₂—),2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—), pentamethylene(—CH₂CH₂CH₂CH₂CH₂—) and the like).

“Alkylidene” means a straight or branched saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.C_(X) alkylidene and C_(X-Y) alkylidene are typically used where X and Yindicate the number of carbon atoms in the chain. For example, C₁₋₆alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like).

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NHC₁₋₁₀-alkyl, —N(C₁₋₁₀-alkyl)₂, —NHaryl, —NHheteroaryl, —N(aryl)₂,—N(heteroaryl)₂, and the like. Optionally, the two substituents togetherwith the nitrogen may also form a ring. Unless indicated otherwise, thecompounds of the invention containing amino moieties may includeprotected derivatives thereof. Suitable protecting groups for aminomoieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and thelike.

“Aminoalkyl” means an alkyl, as defined above, except where one or moresubstituted or unsubstituted nitrogen atoms (—N—) are positioned betweencarbon atoms of the alkyl. For example, an (C₂₋₆) aminoalkyl refers to achain comprising between 2 and 6 carbons and one or more nitrogen atomspositioned between the carbon atoms.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (see Heteroaryl).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. C_(X) aryl and C_(X-Y) aryl are typically used where Xand Y indicate the number of atoms in the ring.

“Bicycloalkyl” means a saturated or partially unsaturated fused bicyclicor bridged polycyclic ring assembly.

“Bicycloaryl” means a bicyclic ring assembly wherein the rings arelinked by a single bond or fused and at least one of the ringscomprising the assembly is aromatic. C_(X) bicycloaryl and C_(X-Y)bicycloaryl are typically used where X and Y indicate the number ofcarbon atoms in the bicyclic ring assembly and directly attached to thering.

“Bridging ring” as used herein refers to a ring that is bonded toanother ring to form a compound having a bicyclic structure where tworing atoms that are common to both rings are not directly bound to eachother. Non-exclusive examples of common compounds having a bridging ringinclude borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the like.One or both rings of the bicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NR_(a)R_(b) where R_(a) and R_(b)are each independently two further substituents where a hydrogen orcarbon atom is attached to the nitrogen.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbocyclic ketone derivative” means a carbocyclic derivative whereinthe ring contains a —CO— moiety.

“Carbonyl” means the radical —CO—. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —CO₂—. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, fused bicyclic or bridged polycyclic ring assembly. C_(X)cycloalkyl and C_(X-Y) cycloalkyl are typically used where X and Yindicate the number of carbon atoms in the ring assembly. For example,C₃₋₁₀ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl,adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl,thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like.

“Cycloalkylene” means a divalent saturated or partially unsaturated,monocyclic or polycyclic ring assembly. C_(X) cycloalkylene and C_(X-Y)cycloalkylene are typically used where X and Y indicate the number ofcarbon atoms in the ring assembly.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure when the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.halo-substituted (C₁₋₃)alkyl includes chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—N═, —NR_(c)—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R_(c) is furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom.

“Heteroaryl” means a cyclic aromatic group having five or six ringatoms, wherein at least one ring atom is a heteroatom and the remainingring atoms are carbon. The nitrogen atoms can be optionallyquaternerized and the sulfur atoms can be optionally oxidized.Heteroaryl groups of this invention include, but are not limited to,those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole,oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole andtetrazole. “Heteroaryl” also includes, but is not limited to, bicyclicor tricyclic rings, wherein the heteroaryl ring is fused to one or tworings independently selected from the group consisting of an aryl ring,a cycloalkyl ring, a cycloalkenyl ring, and another monocyclicheteroaryl or heterocycloalkyl ring. These bicyclic or tricyclicheteroaryls include, but are not limited to, those derived frombenzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine,quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine,thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline,isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine,indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole,benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S. Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like.

“Hydroxy” means the radical —OH.

“Iminoketone derivative” means a derivative comprising the moiety—C(NR)—, wherein R comprises a hydrogen or carbon atom attached to thenitrogen.

“Isomers” mean any compound having an identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed“stereoisomers.”Stereoisomers that are not mirror images of one anotherare termed “diastereomers” and stereoisomers that are nonsuperimposablemirror images are termed “enantiomers” or sometimes “optical isomers.” Acarbon atom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or moreoxygen atoms (—O—) are positioned between carbon atoms of the alkyl. Forexample, an (C₂₋₆)oxaalkyl refers to a chain comprising between 2 and 6carbons and one or more oxygen atoms positioned between the carbonatoms.

“Oxoalkyl” means an alkyl, further substituted with a carbonyl group.The carbonyl group may be an aldehyde, ketone, ester, amide, acid oracid chloride.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of inhibitors of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have kinase inhibitory activity. For example, aninhibitor comprising a hydroxy group may be administered as an esterthat is converted by hydrolysis in vivo to the hydroxy compound.Suitable esters that may be converted in vivo into hydroxy compoundsinclude acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,esters of amino acids, and the like. Similarly, an inhibitor comprisingan amine group may be administered as an amide that is converted byhydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted.

“Sulfinyl” means the radical —SO—. It is noted that the sulfinyl radicalmay be further substituted with a variety of substituents to formdifferent sulfinyl groups including sulfinic acids, sulfinamides,sulfinyl esters, and sulfoxides.

“Sulfonyl” means the radical —SO₂—. It is noted that the sulfonylradical may be further substituted with a variety of substituents toform different sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thiocarbonyl” means the radical —CS—. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a C₁ alkyl comprisesmethyl (i.e., —CH₃) as well as —CR_(a)R_(b)R_(c) where R_(a), R_(b), andR_(c) may each independently be hydrogen or any other substituent wherethe atom attached to the carbon is a heteroatom or cyano. Hence, CF₃,CH₂OH and CH₂CN, for example, are all C₁ alkyls.

Kinase Inhibitors

In one embodiment, kinase inhibitors of the present invention compriseone of the following formula:

wherein:

-   -   R₁ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₂ is selected from the group consisting of hydrogen,        (C₁₋₆)alkyl or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, trifluoromethoxy, and        aryl(C₁₋₁₂)alkyl, each unsubstituted or substituted, with the        proviso that R₃ is not hetero(C₂₋₁₂)cycloalkyl,        hetero(C₄₋₁₂)bicycloaryl, or heteroaryl when Q is CO;    -   Q is selected from the group consisting of CO, CS, and C═NR₄;    -   U is selected from the group consisting of CR₅ or N;    -   V is selected from the group consisting of CR₆ or N;    -   W is selected from the group consisting of CR₇ or N;    -   X is selected from the group consisting of CR₈ or N;    -   Y is selected from the group consisting of CR₉ or N;    -   Z is selected from the group consisting of CR₁₀ or N;    -   R₄ is selected from the group consisting of hydrogen and        unsubstituted or substituted (C₁₋₃)alkyl;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino        (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or R₅ and R₆ are taken together to        form an unsubstituted or substituted ring; and    -   R₇, R₈, R₉, and R₁₀ are each independently selected from the        group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino,        nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted, or R₆ and R₇, R₇ and R₈, R₈ and R₉, R₉ and R₁₀, or        R₁₀ and R₁ are taken together to form an unsubstituted or        substituted ring.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   R₁ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₂ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted, with the proviso that R₃ is not        hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, or heteroaryl        when Q is CO;    -   Q is selected from the group consisting of CO, CS, and C═NR₄;    -   R₄ is selected from the group consisting of hydrogen and        unsubstituted or substituted (C₁₋₃)alkyl;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino        (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or R₅ and R₆ are taken together to        form an unsubstituted or substituted ring;    -   R₇, R₈, and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted, or R₆ and R₇, R₇ and R₈, or R₈ and R₉ are taken        together to form an unsubstituted or substituted ring; and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and        (C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀,        or R₁₀ and R₁ are taken together to form an unsubstituted or        substituted ring.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   R₁ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₂ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted;    -   U is selected from the group consisting of CR₅ or N;    -   V is selected from the group consisting of CR₆ or N;    -   W is selected from the group consisting of CR₇ or N;    -   X is selected from the group consisting of CR₈ or N;    -   Y is selected from the group consisting of CR₉ or N;    -   Z is selected from the group consisting of CR₁₀ or N;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or R₅ and R₆ are taken together to        form an unsubstituted or substituted ring;    -   R₇, R₈, and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted, or R₆ and R₇, R₇ and R₈, or R₈ and R₉ are taken        together to form an unsubstituted or substituted ring; and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and        (C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀,        or R₁₀ and R₁ are taken together to form an unsubstituted or        substituted ring.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   R₂ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted, with the proviso that R₃ is not        hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, or heteroaryl        when Q is CO;    -   Q is selected from the group consisting of CO, CS, and C═NR₄;    -   U is selected from the group consisting of CR₅ or N;    -   V is selected from the group consisting of CR₆ or N;    -   W is selected from the group consisting of CR₇ or N;    -   X is selected from the group consisting of CR₈ or N;    -   Y is selected from the group consisting of CR₉ or N;    -   Z is selected from the group consisting of CR₁₀ or N;    -   R₄ is selected from the group consisting of hydrogen and        unsubstituted or substituted (C₁₋₃)alkyl;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino        (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or R₅ and R₆ are taken together to        form an unsubstituted or substituted ring;    -   R₇, R₈, and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted, or R₆ and R₇, R₇ and R₈, or R₈ and R₉ are taken        together to form an unsubstituted or substituted ring; and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and        (C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀,        or R₁₀ and R₁ are taken together to form an unsubstituted or        substituted ring.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   R₁ is selected from the group consisting of hydrogen or a        substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted, with the proviso that R₃ is not        hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, or heteroaryl        when Q is CO;    -   Q is selected from the group consisting of CO, CS, and C═NR₄;    -   U is selected from the group consisting of CR₅ or N;    -   V is selected from the group consisting of CR₆ or N;    -   W is selected from the group consisting of CR₇ or N;    -   X is selected from the group consisting of CR₈ or N;    -   Y is selected from the group consisting of CR₉ or N;    -   Z is selected from the group consisting of CR₁₀ or N;    -   R₄ is selected from the group consisting of hydrogen and        unsubstituted or substituted (C₁₋₃)alkyl;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino        (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or R₅ and R₆ are taken together to        form an unsubstituted or substituted ring;    -   R₇, R₈, and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted, or R₆ and R₇, R₇ and R₈, or R₈ and R₉ are taken        together to form an unsubstituted or substituted ring; and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and        (C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀,        or R₁₀ and R₁ are taken together to form an unsubstituted or        substituted ring.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted, with the proviso that R₃ is not        hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, or heteroaryl        when Q is CO;    -   R₆ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted; and    -   R₈ and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted.

In yet another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   Q₁ is selected from the group consisting of CH₂, S, SO, SO₂, O,        and NR₁₃;    -   U₁, V₁, W₁, X₁, Y₁, and Z₁ are each independently selected from        the group consisting of CR₁₂ and N;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted, with the proviso that R₃ is not        hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, or heteroaryl        when Q is CO;    -   R₆ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted;    -   R₈ and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted;    -   R₁₁ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or any two R₁₁ are taken together        to form a substituted or unsubstituted ring;    -   R₁₂ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted; and    -   R₁₃ is selected from the group consisting of hydrogen,        halo(C₁₋₁₀)alkyl, amino, sulfonamide, (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl,        aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, sulfonyl, and sulfinyl, each unsubstituted or        substituted.

In another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   Q₁ is selected from the group consisting of CH₂, S, SO, SO₂, O,        and NR₁₃;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted;    -   R₈ and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted;    -   R₁₁ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or any two R₁₁ are taken together        to form a substituted or unsubstituted ring; and    -   R₁₃ is selected from the group consisting of hydrogen,        halo(C₁₋₁₀)alkyl, amino, sulfonamide, (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl,        aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, sulfonyl, and sulfinyl, each unsubstituted or        substituted.

In still another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   Q₁ is selected from the group consisting of CH₂, S, SO, SO₂, O,        and NR₁₃;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted;    -   R₈ and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino        group, sulfonyl group and sulfinyl group, each unsubstituted or        substituted;    -   R₁₁ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or any two R₁₁ are taken together        to form a substituted or unsubstituted ring; and    -   R₁₃ is selected from the group consisting of hydrogen,        halo(C₁₋₁₀)alkyl, amino, sulfonamide, (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl,        aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, sulfonyl, and sulfinyl, each unsubstituted or        substituted.

In yet another embodiment, kinase inhibitors of the present inventioncomprise the formula:

wherein:

-   -   Q₁ is selected from the group consisting of CH₂, S, SO, SO₂, O,        and NR₁₃;    -   R₃ is selected from the group consisting of hydrogen,        (C₁₋₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl,        heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl,        sulfinyl, halo, cyano, nitro, and trifluoromethoxy, each        unsubstituted or substituted;    -   R₈ and R₉ are each independently selected from the group        consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro,        cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₃)alkyl, heteroaryl(C₁₋₅)alkyl,        (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl,        aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl group, imino group, sulfonyl group and sulfinyl group,        each unsubstituted or substituted;    -   R₁₁ is selected from the group consisting of hydrogen, halo,        halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,        (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino,        amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, each        unsubstituted or substituted, or any two R₁₁ are taken together        to form a substituted or unsubstituted ring; and    -   R₁₃ is selected from the group consisting of hydrogen,        halo(C₁₋₁₀)alkyl, amino, sulfonamide, (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl,        aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, sulfonyl, and sulfinyl, each unsubstituted or        substituted.

In one variation of the above embodiments, R₁₁ is selected from thegroup consisting of arylsulfonyl, heteroarylsulfonyl, arylamino,heteroarylamino, arylthio, and heteroarylthio, each unsubstituted orsubstituted.

The compound according to claim 11, wherein R₁₁ is substituted with asubstituent selected from the group consisting of

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.

In one variation of each of the above embodiments, R₅ is selected fromthe group consisting of arylthio, heteroarylthio, (C₁₋₁₀)alkylthio,sulfonylaryl and sulfonylheteroaryl, each unsubstituted or substituted.

In one variation of each of the above embodiments, R₆ is selected fromthe group consisting of hydrogen, halo, alkoxy and thio, eachunsubstituted or substituted. In another variation, R₆ is selected fromthe group consisting of arylthio, heteroarylthio, (C₁₋₁₀)alkylthio,sulfonylaryl and sulfonylheteroaryl, each unsubstituted or substituted.In a further variation, R₆ is an unsubstituted or substitutedphenylthio. In another variation, R₆ is selected from the groupconsisting of arylsulfonyl, heteroarylsulfonyl, arylamino,heteroarylamino, arylthio, and heteroarylthio, each unsubstituted orsubstituted. In a further variation, R₆ is selected from the groupconsisting of arylsulfonyl, heteroarylsulfonyl, arylamino,heteroarylamino, arylthio, and heteroarylthio, each substituted with asubstituent selected from the group consisting of:

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy. In still another variation, R₆ is acarboxamidophenylthio. In another variation of each of the aboveembodiments and variations, R₈ is selected from the group consisting ofhydrogen, halo, alkoxy and thio, each unsubstituted or substituted. Inanother variation of each of the above embodiments and variations, R₈ isselected from the group consisting of hydrogen; —O—(C₁₋₆)alkylamino;hydroxy; halo; trifluoromethyl; cyano; mercapto; nitro; amino; carboxy;carbamoyl; formyl; sulphamoyl; (C₁₋₆)alkyl; (C₁₋₆)alkoxy;—O—(C₁₋₃)alkyl-O—; —(C₁₋₆)alkyl-S(O)_(n), wherein n is 0, 1 or 2;—(C₁₋₆)alkylamino; —(C₁₋₆)dialkylamino; —(C₁₋₆)alkoxycarbonyl;—(C₁₋₆)alkylcarbamoyl; —(C₁₋₆)dialkylcarbamoyl; —(C₂₋₆)alkanoyl;—(C₁₋₆)alkanoyloxy; —(C₁₋₆)alkanoylamino; —(C₁₋₆)alkylsulphamoyl;—(C₁₋₆)dialkylsulphamoyl; —(C₁₋₆)alkylsulphonylamino;—(C₁₋₆)alkylsulphonyl-(C₁₋₆)alkyl-amino, each unsubstituted orsubstituted.

In another variation of each of the above embodiments and variations, atleast one of R₈ and R₉ is —B—(CH₂)_(p)—A, wherein:

-   -   A is selected from the group consisting of halo; hydroxy;        (C₁₋₆)alkoxy; (C₁₋₆)alkyl-S(O)_(n) wherein n is 0, 1 or 2;        cyano; amino; (C₁₋₆)alkylamino; (C₁₋₆)dialkylamino; carboxy;        (C₁₋₆)alkoxycarbonyl; carbamoyl; (C₁₋₆)alkylcarbamoyl; and        (C₁₋₆)dialkylcarbamoyl, each unsubstituted or substituted;    -   p is 0, 1, 2,3,4,5, or 6; and    -   B is selected from the group consisting of a bond; oxa; imino;        thia; (C₁₋₆)alkylamino; and —C(O)NH—, each unsubstituted or        substituted.

In another variation of each of the above embodiments and variations, atleast one of R₈ and R₉ is —E—D, wherein:

-   -   D is selected from the group consisting of aryl, heteroaryl or        heterocyclyl, each unsubstituted or substituted; and    -   E is selected from the group consisting of a bond;        (C₁₋₆)alkylene; (C₁₋₆)alkyleneoxy; oxy; imino; (C₁₋₆)alkylamino;        (C₁₋₆)alkyleneimino; (C₁₋₆)alkyl-(C₁₋₆)alkyleneimino;        (C₁₋₆)alkyleneoxy-(C₁₋₆)alkylene;        (C₁₋₆)alkyleneimino-(C₁₋₆)alkylene;        (C₁₋₆)alkyl-(C₁₋₆)alkyleneimino-(C₁₋₆)alkylene; —C(O)NH—;        —SO₂—NH—; —NH—SO₂—; or (C₂₋₆)alkanoylimino, each unsubstituted        or substituted.

In a further variation of each of the above embodiments and variations,R₈ is hydrogen.

In still a further variation of each of the above embodiments andvariations, R₉ is hydrogen.

In a further variation of each of the above embodiments and variations,R₁ is hydrogen.

Further, in each of the above embodiments and variations, R₂ isoptionally hydrogen.

In yet another variation of each of the above embodiments andvariations, R₃ is selected from the group consisting of hydrogen,(C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy,aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro,and trifluoromethoxy, each unsubstituted or substituted. In stillanother variation, R₃ is selected from the group consisting of methyl,ethyl, propyl, cyclopropyl, and isopropyl.

In still a further variation of each of the above embodiments andvariations, Q is CO. In another variation, Q is S. In yet anothervariation Q₁ is CO. In still another variation, Q₁ is S.

Particular examples of kinase inhibitors according to the presentinvention include, but are not limited to:

-   (Z)-3-methyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-(6-aminopyridin-3-ylamino)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-ethoxyquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-3-methyl-4-(4-(phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-6-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)nicotinic    acid;-   (Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;-   (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-ethyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-ethyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;-   (Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;-   (Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide;-   (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide;-   (Z)-2-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)benzamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclobutanecarboxamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopentanecarboxamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)furan-2-carboxamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)thiophene-2-carboxamide;-   (Z)-2-methoxy-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propionamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butyramide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;-   (Z)-2-methoxyethyl    4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenylcarbamate;-   (Z)-3-(methylthio)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide;-   (Z)-4-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butanamide;-   (Z)-3-(diethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)isobutyramide;-   (R,Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)pyrrolidine-2-carboxamide;-   (Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)piperidine-4-carboxamide;-   (Z)—N-(4-(6-methoxy-2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(4-aminophenylthio)-6-methoxyquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-6-methoxy-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)—N-(4-(2-(3-cyclohexyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylsulfonyl)phenyl)propionamide;-   (Z)-5-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylamino)-1H-indazol-3(2H)-one;-   (Z)—N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide;-   (Z)-3-phenyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)—N-methyl-4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide;-   (Z)-3-cyclopropyl-4-(isoquinolin-1    (2H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(1-methyl-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)—N-(3-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)phenyl)methanesulfonamide;-   (Z)-3-amino-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   ((Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;-   (Z)-3-benzyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-3-benzyl-4-(4-phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)—N-(4-(2-(3-benzyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;-   (Z)-4-(4-(2-methoxyphenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-3-methyl-4-(4-(m-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-methyl    3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate;-   (Z)-methyl    2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate;-   (Z)-3-methyl-4-(4-(o-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-methyl    3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoic    acid;-   (Z)-3-methyl-4-(4-(4-nitrophenyl)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-(2-hydroxyphenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   3-cyclopropyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one;-   3-((Z)-5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acrylamide;-   3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)propanamide;-   2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)cyclopropanecarboxamide;-   N-methyl-2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)cyclopropane-1-sulfonamide;-   3-(4-aminobenzyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   3-(4-aminophenylamino)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   3-(4-aminophenylthio)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)acetamide;-   N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-ylamino)phenyl)acetamide;-   N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-ylthio)phenyl)acetamide;-   3-amino-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acetamide;-   1-methyl-3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)urea;-   1-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)-3-phenylurea;-   2-(4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide;-   2-(4-(6-(2-(diethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide;-   N-methyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzenesulfonamide;-   (Z)-3-(2-(ethylsulfonyl)cyclopropyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-3-(2-(ethylsulfonyl)cyclopropyl)-1H-pyrazol-5(4H)-one;-   (Z)—N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzamide;-   (Z)-3-(ethylsulfonyl)-N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzamide;-   (Z)-4-(4-(3-(ethylsulfonyl)phenyl)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-4-(4-(1-(ethylsulfonyl)-1H-indol-4-yl)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;-   (Z)-2-((3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile;-   (Z)-2-((4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile;-   (Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-4-yl)methyl)benzonitrile;-   (Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-5-yl)methyl)benzonitrile;-   (Z)-2-((5-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile;-   (Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinoline-4-carbonyl)phenyl)cyclopropanecarboxamide;-   (Z)—N-(4-((2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)methyl)phenyl)cyclopropanecarboxamide;-   (Z)—N-(2-ethyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;-   (Z)—N-(2-methoxy-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;-   (Z)-3-(4-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-3-(3-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)-3-(1-(ethylsulfonyl)-1H-indol-5-yl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;-   (Z)—N-cyclopropyl-2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)thiazole-5-carboxamide;    and-   (Z)—N-(2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)thiazol-5-yl)cyclopropanecarboxamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas a hydrogen.

It is further noted that the compounds of the present invention mayoptionally be solely or predominantly in the enol tautomer in its activestate. It is further noted that the compound may be present in a mixtureof stereoisomers, or the compound comprises a single stereoisomer.

The invention also provides pharmaceutical compositions comprising, asan active ingredient, a compound according to any one of the aboveembodiments and variations. In addition, the composition may be a solidor liquid formulation adapted for oral administration. In a furthervariation, the pharmaceutical composition may be a tablet. In yetanother variation, the pharmaceutical composition may be a liquidformulation adapted for parenteral administration.

In one embodiment, there is provided the pharmaceutical compositioncomprising a compound according to each of the above variations whereinthe composition is adapted for administration by a route selected fromthe group consisting of orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, and intrathecally.

The invention also provides a kit comprising a compound or compositionaccording to any one of the above embodiments and variations, andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecompound is to be administered, storage information for the compound,dosing information and instructions regarding how to administer thecompound.

In one variation, the kit comprises the compound or composition in amultiple dose form.

In another embodiment, the present invention provides an article ofmanufacture comprising a compound or composition according to any one ofthe above embodiments and variations, and packaging materials.

In one variation, the packaging material comprises a container forhousing the compound or composition. The container optionally comprisesa label indicating a disease state for which the compound or compositionis to be administered, storage information, dosing information and/orinstructions regarding how to administer the compound or composition.

In regard to the above embodiments and variations, the article ofmanufacture optionally comprises the compound or composition in amultiple dose form.

In yet another embodiment, the present invention provides a method ofinhibiting kinase comprising contacting kinase with a compound orcomposition according to any one of the above embodiments andvariations.

In one variation, the inhibition arises from a favorable conformationadopted by the compound in its enol form, and the conformation arisesfrom an intramolecular hydrogen bonding of the enol hydrogen and anadjacent nitrogen atom of the compound.

In another variation, the inhibition arises from a favorableconformation adopted by the compound in its enol form, and theinhibition arises from a hydrogen bonding interaction between the enoltautomer and an active site residue of the kinase.

In still another embodiment, there is provided a method of inhibitingkinase comprising causing a compound or composition according to any oneof the above embodiments and variations to be present in a subject inorder to inhibit kinase in vivo.

The present invention also provides a method of inhibiting kinasecomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits kinasein vivo, the second compound being a compound according to any one ofthe above embodiments and variations.

In another embodiment, the present invention provides a therapeuticmethod comprising administering a compound or composition according toany one of the above embodiments and variations to a subject.

In yet another embodiment, there is provided a method of treating adisease state for which kinase possesses activity that contributes tothe pathology and/or symptomology of the disease state comprisingcausing a compound or composition according to any one of the aboveembodiments and variations to be present in a subject in atherapeutically effective amount for the disease state.

The present invention also provides a method of treating a disease statefor which kinase possesses activity that contributes to the pathologyand/or symptomology of the disease state comprising administering afirst compound to a subject that is converted in vivo to a secondcompound according to any one of the above embodiments and variationswherein the second compound is present in a subject in a therapeuticallyeffective amount for the disease state.

In addition, there is provided a method of treating a disease state forwhich kinase possesses activity that contributes to the pathology and/orsymptomology of the disease state comprising administering a compound orcomposition according to any one of the above embodiments andvariations, wherein the compound or composition is present in thesubject in a therapeutically effective amount for the disease state.

In another embodiment, there is provided a method for treating cancercomprising administration to a mammalian species in need thereof of atherapeutically effective amount of a composition of the presentinvention. In one embodiment, the cancer is selected from the groupconsisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma,glioblastoma, non small-cell lung cancer, bladder cancer, head and neckcancer, melanoma, ovarian cancer, prostate cancer, breast cancer,small-cell lung cancer, glioma, colorectal cancer, genitourinary cancerand gastrointestinal cancer.

In another embodiment, there is provided a method of treating a diseasestate for which kinase possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: causing a compound or composition according to the presentinvention to be present in a subject in a therapeutically effectiveamount for the disease state.

In another embodiment, there is provided a method for treatinginflammation, inflammatory bowel disease, psoriasis, or transplantrejection, comprising administration to a mammalian species in needthereof of a therapeutically effective amount of a compound orcomposition according to the present invention.

In yet another embodiment, the present invention provides a method ofpreventing or treating a disease state for which kinase possessesactivity that contributes to the pathology and/or symptomology of thedisease state, the method comprising: administering a first compound toa subject that is converted in vivo to a second compound according toany one of the compounds or compositions of the present inventionwherein the second compound is present in a subject in a therapeuticallyeffective amount for the disease state.

In yet another embodiment, there is provided a method of preventing ortreating a disease state for which kinase possesses activity thatcontributes to the pathology and/or symptomology of the disease state,the method comprising: administering a compound or composition of thepresent invention, wherein the compound is present in the subject in atherapeutically effective amount for the disease state.

In a further embodiment, there is provided a method for preventing ortreating dementia related diseases and Alzheimer's Disease, comprisingadministration to a mammalian species in need thereof of atherapeutically effective amount of a compound or composition accordingto any one of the above embodiments. In one particular variation, thedementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica.

In another embodiment, there is provided a method for preventing ortreating amyotrophic lateral sclerosis, corticobasal degeneration, Downsyndrome, Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication, comprising administration to a mammalianspecies in need thereof of a therapeutically effective amount of acompound or composition according to any one of the above embodiments.

In yet another embodiment, there is provided a method for preventing ortreating mild Cognitive Impairment, Age-Associated Memory Impairment,Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mildcognitive decline, mild neurocognitive decline, Late-Life Forgetfulness,memory impairment and cognitive impairment and androgenetic alopecia,comprising administering to a mammal, including man in need of suchprevention and/or treatment, a therapeutically effective amount of acompound or composition according to any one of the above embodiments.

In another embodiment, there is provided a method for preventing ortreating dementia related diseases, Alzheimer's Disease and conditionsassociated with kinases, comprising administering to a mammal, includingman in need of such prevention and/or treatment, a therapeuticallyeffective amount of a compound or composition according to the aboveembodiments.

In another embodiment, there is provided a method for treating arthritiscomprising administration to a mammalian species in need thereof of atherapeutically effective amount of a compound or composition accordingto any one of the above embodiment.

In another embodiment, there is provided a method of treating a diseasestate for which kinase possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: administering a first compound to a subject that isconverted in vivo to a second compound or composition according to anyone of the present invention, wherein the second compound is present ina subject in a therapeutically effective amount for the disease state.

In another embodiment, there is provided a method of treating a diseasestate for which kinase possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: administering a compound or composition according to any oneof the above embodiment, wherein the compound is present in the subjectin a therapeutically effective amount for the pathology and/orsymptomology.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate or aprodrug thereof (e.g., where the compound comprises a substituent thatis convertible in vivo to a different substituent such as hydrogen).

It is further noted that the compounds of the present invention mayoptionally be solely or predominantly in the enol tautomer in its activestate.

It is also noted that the compounds of the present invention may bepresent as a mixture of stereoisomers or may be present as a singlestereoisomer.

Salts, Hydrates, and Prodrugs of Kinase Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g. potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; andaryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide.Such salts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier etal.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallization from an aqueous/organic solvent mixture,using organic solvents such as dioxin, tetrahydrofuran or methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Preparation of Kinase Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (enantiomers, diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) that they can be readily separated bytaking advantage of these dissimilarities. For example, diastereomerscan typically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Composition Comprising Kinase Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the kinase inhibitors of the present invention. Suchcompositions may include, in addition to the kinase inhibitors of thepresent invention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the kinaseinhibitors of the present invention. These additional active agents mayinclude additional compounds according to the invention, and/or one ormore other pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising kinase inhibitors of the present invention maybe administered or coadministered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compoundsand/or compositions according to the invention may also be administeredor coadministered in slow release dosage forms.

The kinase inhibitors and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a kinase inhibitor, in the course of a coordinated treatment toachieve an improved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When kinase inhibitors according to the present invention exhibitinsufficient solubility, methods for solubilizing the compounds may beused. Such methods are known to those of skill in this art, and include,but are not limited to, using cosolvents, such as dimethylsulfoxide(DMSO), using surfactants, such as TWEEN, or dissolution in aqueoussodium bicarbonate. Derivatives of the compounds, such as prodrugs ofthe compounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding kinase inhibitors according to the presentinvention to a composition, a solution, suspension, emulsion or the likemay be formed. The form of the resulting composition will depend upon anumber of factors, including the intended mode of administration, andthe solubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more kinase inhibitors according to the presentinvention, the composition may comprise: a diluent such as lactose,sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant,such as magnesium stearate, calcium stearate and talc; and a binder suchas starch, natural gums, such as gum acaciagelatin, glucose, molasses,polyinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of a kinase inhibitor of thepresent invention to reduce kinases activity in vivo, thereby treatingthe disease state of the subject.

Dosage forms or compositions may optionally comprise one or more kinaseinhibitors according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more kinase inhibitors, optionally 0.1-95%,and optionally 1-95%.

Salts, preferably sodium salts, of the kinase inhibitors may be preparedwith carriers that protect the compound against rapid elimination fromthe body, such as time release formulations or coatings. Theformulations may further include other active compounds to obtaindesired combinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, kinase inhibitors according to the presentinvention are provided as solid dosage forms, preferably capsules ortablets. The tablets, pills, capsules, troches and the like mayoptionally contain one or more of the following ingredients, orcompounds of a similar nature: a binder; a diluent; a disintegratingagent; a lubricant; a glidant; a sweetening agent; and a flavoringagent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The kinase inhibitors of the present invention may also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising kinase inhibitors of the present invention include,but are not limited to binders, lubricants, diluents, disintegratingagents, coloring agents, flavoring agents, and wetting agents.Enteric-coated tablets, because of the enteric-coating, resist theaction of stomach acid and dissolve or disintegrate in the neutral oralkaline intestines. Sugar-coated tablets may be compressed tablets towhich different layers of pharmaceutically acceptable substances areapplied. Film-coated tablets may be compressed tablets that have beencoated with polymers or other suitable coating. Multiple compressedtablets may be compressed tablets made by more than one compressioncycle utilizing the pharmaceutically acceptable substances previouslymentioned. Coloring agents may also be used in tablets. Flavoring andsweetening agents may be used in tablets, and are especially useful inthe formation of chewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g. water, tobe easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g. propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the kinase inhibitors of the present invention by parenteraladministration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously. Injectables may beprepared in any conventional form, for example as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions include EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of a kinase inhibitor in the parenteral formulationmay be adjusted so that an injection administers a pharmaceuticallyeffective amount sufficient to produce the desired pharmacologicaleffect. The exact concentration of a kinase inhibitor and/or dosage tobe used will ultimately depend on the age, weight and condition of thepatient or animal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is know and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the kinase inhibitor to the treatedtissue(s). The kinase inhibitor may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment will be a function of the location of where the composition isparenterally administered, the carrier and other variables that may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens may need to be adjustedover time according to the individual need and the professional judgmentof the person administering or supervising the administration of theformulations. Hence, the concentration ranges set forth herein areintended to be exemplary and are not intended to limit the scope orpractice of the claimed formulations.

The kinase inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The kinase inhibitors of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a kinase inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the kinase inhibitor.

Topical Administration

The kinase inhibitors of the present invention may also be administeredas topical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The kinase inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The kinase inhibitors may also be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye or for intracisternal or intraspinalapplication. Topical administration is contemplated for transdermaldelivery and also for administration to the eyes or mucosa, or forinhalation therapies. Nasal solutions of the kinase inhibitor alone orin combination with other pharmaceutically acceptable excipients canalso be administered.

Formulations for Other Routes of Administrations

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mLINTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL TABLETFORMULATION Compound of the Present Invention  1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica   1%.Kits Comprising Kinase Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with kinases. It is noted that diseasesare intended to cover all conditions for which the kinases possessesactivity that contributes to the pathology and/or symptomology of thecondition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one kinase inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one kinase inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

EXAMPLES 1. Preparation of Kinase Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (enantiomers, diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) that they can be readily separated bytaking advantage of these dissimilarities. For example, diastereomerscan typically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g. hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

-   -   g (grams); mg (milligrams);    -   L (liters); mL (milliliters);    -   μL (microliters); psi (pounds per square inch);    -   M (molar); mM (millimolar);    -   i.v. (intravenous); Hz (Hertz);    -   MHz (megahertz); mol (moles);    -   mmol (millimoles); RT (ambient temperature);    -   min (minutes); h (hours);    -   mp (melting point); TLC (thin layer chromatography);    -   Tr (retention time); RP (reverse phase);    -   MeOH (methanol); i-PrOH (isopropanol);    -   TEA (triethylamine); TFA (trifluoroacetic acid);    -   TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);    -   DMSO (dimethylsulfoxide); EtOAc (ethyl acetate);    -   DME (1,2-dimethoxyethane); DCM (dichloromethane);    -   DCE (dichloroethane); DMF (N,N-dimethylformamide);    -   DMPU (N,N′-dimethylpropyleneurea); CDI        (1,1-carbonyldiimidazole);    -   IBCF (isobutyl chloroformate); HOAc (acetic acid);    -   HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole);    -   Et₂O (diethyl ether); EDCI (ethylcarbodiimide hydrochloride);    -   BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl);    -   DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);    -   Ac (acetyl); atm (atmosphere);    -   TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);    -   TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);    -   DMAP (4-dimethylaminopyridine); Me (methyl);    -   OMe (methoxy); Et (ethyl);    -   Et (ethyl); tBu (tert-butyl);    -   HPLC (high pressure liquid chromatography);    -   BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);    -   TBAF (tetra-n-butylammonium fluoride);    -   mCPBA (meta-chloroperbenzoic acid.

All references to ether or Et₂O are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsconducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosure of all documents cited throughout this applicationare incorporated herein by reference.

2. Synthetic Schemes for Kinase Inhibitors of the Present Invention

Kinase inhibitors according to the present invention may be synthesizedaccording to the reaction scheme shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Kinase inhibitors according to the present invention may be synthesizedaccording to the reaction scheme shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Condensation of β-ketoesters with quinoline-N-oxides

A quinoline N-oxide (compound A) and an acetoacetate (1:1) are dissolvedin an acetic anhydride. The resulting solution can then be stirred at,for example, a temperature of between room temperature and 120° C. forbetween 0.5-2 hours to form compound B. The solution can then be cooledto room temperature and concentrated in vacuo. Compound B may beprecipitated in ether, isolated by filtration, and dried in vacuo.

Cyclization to Pyrazolinones

A solution of compound B in ethanol is treated with hydrazine. Aceticacid (5-20%) is added and the reaction mixture stirred at, for example,ambient temperature for 6-20 hrs to form compound C. Compound C can beisolated by filtration, washed with a small amount of ethanol, and thendried in vacuo.

Nucleophilic Aromatic Substitutions

A 1:1 mixture of compound C and a nucleophile in ethanol is heated at,for example, 50-250° C. for 1-30 minutes using a microwave reactor toform compound D. If a solid is observed upon cooling, the material maybe isolated by filtration. Alternatively, if a solid is not formed, themixture can be concentrated and purified using, for example, LC-MS.

Cyclization to Pyrazole

A solution of β-ketoester (compound E) in ethanol is treated withhydrazine. Acetic acid (5-20%) is added and the reaction mixture maythen be stirred at, for example, ambient temperature for 1-5 hrs to formcompound F. The resulting solid may be isolated by filtration, washedwith a small amount of ethanol, and then dried in vacuo.

Condensation of Pyrazole with quinoline-N-oxides

A quinoline N-oxide and compound F (1:1) are dissolved in an aceticanhydride. The resulting solution may be stirred at, for example, roomtemperature for between 0.5-2 hours to form compound C. Compound C canbe filtered and dried in vacuo.

Nucleophilic Aromatic Substitutions

A 1:1 mixture of compound C and a nucleophile in ethanol is heated at,for example, 50-250° C. for 1-30 minutes using a microwave reactor toform compound D. If a solid is observed upon cooling, the material maybe isolated by filtration. Alternatively, if a solid is not formed, themixture can be concentrated and purified using, for example, LC-MS.

It will be apparent to those skilled in the art that variations to theabove reaction schemes can be utilized. For example, in reaction schemeA, the step of cyclizing the pyrazole can be carried out prior to thestep of condensing with the quinoline moiety.

For example, the above reaction scheme, and variations thereof, can beused to prepare the following:

3-cyclopropyl-4-(quinolin-2(1H)-ylidene)-1H- pyrazol-5(4H)-one

4-(4-chloroquinolin-2(1H)-ylidene)-3- cyclopropyl-1H-pyrazol-5(4H)-one

3-((Z)-5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acrylamide

3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)propanamide

2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5- dihydro-1H-pyrazol-3-yl)cyclopropanecarboxamide

N-methyl-2-(5-oxo-4-(quinolin-2(1H)- ylidene)-4,5-dihydro-1H-pyrazol-3-yl)cyclopropane-1-sulfonamide

3-(4-aminobenzyl)-4-(quinolin-2(1H)-ylidene)- 1H-pyrazol-5(4H)-one

3-(4-aminophenylamino)-4-(quinolin-2(1H)- ylidene)-1H-pyrazol-5(4H)-one

3-(4-aminophenylthio)-4-(quinolin-2(1H)- ylidene)-1H-pyrazol-5(4H)-one

N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5- dihydro-1H-pyrazol-3-yl)methyl)phenyl)acetamide

N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5- dihydro-1H-pyrazol-3-ylamino)phenyl)acetamide

N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-ylthio)phenyl)acetamide

3-amino-4-(quinolin-2(1H)-ylidene)-1H- pyrazol-5(4H)-one

N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acetamide

1-methyl-3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)urea

1-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)-3-phenylurea

2-(4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide

2-(4-(6-(2-(diethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide

N-methyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4- ylthio)benzenesulfonamide

(Z)-3-(2-(ethylsulfonyl)cyclopropyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)- one

(Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin- 2(1H)-ylidene)-3-(2-(ethylsulfonyl)cyclopropyl)-1H-pyrazol-5(4H)- one

(Z)-N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzamide

(Z)-3-(ethylsulfonyl)-N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3- yl)benzamide

(Z)-4-(4-(3-(ethylsulfonyl)phenyl)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)- one

(Z)-4-(4-(1-(ethylsulfonyl)-1H-indol-4-yl)quinolin-2(1H)-ylidene)-3-methyl-1H- pyrazol-5(4H)-one

(Z)-2-((3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile

(Z)-2-((4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile

(Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-4-yl)methyl)benzonitrile

(Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-5-yl)methyl)benzonitrile

(Z)-2-((5-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile

(Z)-N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinoline-4-carbonyl)phenyl)cyclopropanecarboxamide

(Z)-N-(4-((2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)methyl)phenyl)cyclopropanecarboxamide

(Z)-N-(2-ethyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide

(Z)-N-(2-methoxy-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide

(Z)-3-(4-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

(Z)-3-(3-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

(Z)-3-(1-(ethylsulfonyl)-1H-indol-5-yl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)- one

(Z)-N-cyclopropyl-2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3- yl)thiazole-5-carboxamide

(Z)-N-(2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)thiazol-5- yl)cyclopropanecarboxamide

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction scheme are set forthherein.

3. Examples of Kinase Inhibitors

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Example 1 (Z)-3-methyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

Commercially available Quinoline N-oxide (Aldrich) (145 mg, 1 mmol) andmethyl acetoacetate (0.1 mL, 1 mmol) was dissolved in acetic anhydride(2 mL) and heated at 90° C. for 1-2 hrs. The reaction mixture was cooledto room temperature and concentrated in vacuo, and the residue treatedwith ether. The resulting precipitate was filtered and dried in vacuo.Then, the crude material was dissolved in a mixture of ethanol andacetic acid (10:1, 2 mL) and treated with hydrazine (0.03 mL, 1 mmol).The mixture was stirred at ambient temperature for 18 hrs, and theresulting solid filtered and washed with a minimum amount of ethanol. ¹HNMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H), 7.43-7.54 (m, 1H) 7.71 (t,J=7.33 Hz, 2H) 7.89 (d, J=7.83 Hz, 2H) 8.30 (d, J=8.34 Hz, 1H) 11.14 (s,1H) 11.88 (s, 1H); ESI-MS: m/z calc'd for C₁₃H₁₁N₃O 225.09. found 226.2(M+H)⁺.

Example 2(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

The title compound was prepared from 4-chloroquinoline N-oxide withmethyl acetoacetate, under conditions analogous to those described inExample 1. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H) 7.61 (t, J=7.58Hz, 1H) 7.80 (t, J=7.20 Hz, 1H) 7.96 (d, J=8.34 Hz, 1H) 8.05 (s, 1H)8.09 (d, J=8.08 Hz, 1H) 12.00 (s, 1H) 11.16 (s, 1H); ESI-MS: m/z calc'dfor C₁₃H₁₀ClN₃O 259.05. found 260.2 (M+H)⁺.

Example 3(Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

Triphenyl phosphine (4.3 g, 16.5 mmol) was dissolved in THF (5 mL).Diisopropyl azodicarboxylate (“DIAD”) (3.2 mL, 16.5 mmol) was added dropwise and stirred at room temperature. A mixture of 6-hydroxyquinoline(1.99 g, 13.7 mmol) and 2-bromoethanol (0.97 mL, 13.7 mmol) in THF wasadded to the above mixture. After 2 hrs, the reaction mixture wasconcentrated in vacuo and purified by flash chromatography. Theresulting solid, 6-(2-bromoethoxy) quinoline, was dissolved in DCM (40mL) and treated with mCPBA (3.17 g, 13.8 mmol). After 2 hrs, thereaction mixture was washed with aq HCO₃ ⁻ (10 mL). The organic phasewas washed with brine, dried over anhydrous MgSO₄, and concentrated toyield a solid.

The crude residue (3.7 mmol) was treated with dimethylamine (1.85 mL,3.7 mmol) in ethanol (10 mL) and TEA (0.5 mL), and stirred at 75° C. for12-15 hrs. The reaction mixture was concentrated and the resultingresidue carried out to the next step without further purification. Then,the title compound was synthesized using the above crude product andmethyl acetoacetate according to the procedure described in Example 1.¹H NMR (400 MHz, DMSO-D6) δ ppm 2.53 (s, 3H) 2.89 (s, 6H) 3.59-3.64 (m,2H) 4.41-4.51 (m, 2H) 7.43-7.54 (m, 2H) 7.81 (d, J=8.84 Hz, 1H) 7.94 (d,J=9.09 Hz, 1H) 8.38 (d, J=8.84 Hz, 1H) 9.72 (s, 1H); ESI-MS: m/z calc'dfor C₁₇H₂₀N₄O₂ 312.16. found 313.3 (M+H)⁺.

Example 4(Z)-4-(4-(6-aminopyridin-3-ylamino)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

Example 5(Z)-4-(4-ethoxyquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one(0.033 g, 0.13 mmol) and 2-acetamido-5-aminopyridine (Matrix) (0.058 g,0.38 mmol) were dissolved in ethanol (1.5 mL). The reaction mixture washeated to 180° C. using a microwave reactor for 6 hrs. The mixture wasconcentrated and purified by LC-MS to give the title compounds ofExample 4 and Example 5.

Example 4

¹H NMR (400 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 6.56 (s, 1H) 6.85 (s, 1H)7.69 (s, 1H) 7.80 (d, J=1.26 Hz, 1H) 7.94 (d, J=12.88 Hz, 2H) 8.09 (s,1H) 8.50 (d, J=8.34 Hz, 1H) 10.22 (s, 1H) 13.37 (bs, 1H); ESI-MS: m/zcalc'd for C₁₈H₁₆N₆O 332.14. found 333.3 (M+H)⁺.

Example 5

¹H NMR (400 MHz, DMSO-D6) δ ppm 1.53 (t, J=6.32 Hz, 3H) 2.49 (s, 3H)4.51-4.53 (m, 2H) 6.98 (s, 1H) 7.60 (s, 1H) 7.85-7.91 (m, 2H) 8.13 (d,J=7.83 Hz, 1H); ESI-MS: m/z calc'd for C₁₅H₁₅N₃O₂ 269.12. found 270.2(M+H)⁺.

Example 6(Z)-3-methyl-4-(4-(phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one(0.05 g, 0.19 mmol) and thiophenol (Aldrich) (0.04 mL, 0.38 mmol) weredissolved in ethanol (2 mL). The reaction mixture was heated to 180° C.using a microwave reactor for 20 minutes. The solid was precipitatedupon cooling. The material was filtered and washed with a minimal amountof ethanol, and then dried in vacuo. ¹H NMR (400 MHz, DMSO-D6) δ ppm1.86 (s, 3H) 6.77 (s, 1H) 7.56 (t, J=7.58 Hz, 1H) 7.62 (s, 1H) 7.63 (d,J=2.53 Hz, 2H) 7.71-7.76 (m, 2H) 7.79 (t, J=7.58 Hz, 1H) 7.84-7.89 (m,1H) 8.08 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C₁₉H₁₅N₃OS 333.09.found 334.2 (M+H)⁺.

Example 7(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and4-aminothiophenol using the procedure described in Example 6. ¹H NMR(400 MHz, CHLOROFORM-D) δ ppm 1.97 (s, 3H) 6.77-6.79 (m, 3H) 7.33 (d,J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d,J=8.59 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd forC₁₉H₁₆N₄OS 348.10. found 349.2 (M+H)⁺.

Example 8(Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and4-actamidothiophenol using the procedure described in Example 6. ¹H NMR(400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.11 (s, 3H) 6.77 (s, 1H)7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d,J=8.34 Hz, 1H) 10.35 (s, 1H); ESI-MS: m/z calc'd for C₂₁H₁₈N₄O₂S 390.12.found 391.2 (M+H)⁺.

Example 9(Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and2-thiopyridine using the procedure described in Example 6. ¹H NMR (400MHz, DMSO-D6) δ ppm 2.31 (s, 3H) 7.40 (dd, J=7.20, 4.93 Hz, 1H) 7.55 (t,J=7.58 Hz, 2H) 7.73 (s, 1H) 7.77-7.87 (m, 2H) 7.96 (d, J=8.59 Hz, 1H)8.06 (d, J=8.08 Hz, 1H) 8.58 (d, J=3.79 Hz, 1H); ESI-MS: m/z calc'd forC₁₈H₁₄N₄OS 334.09. found 335.2 (M+H)⁺.

Example 10(Z)-6-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)nicotinicAcid

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and6-mercaptonicotinic acid using the procedure described in Example 6. ¹HNMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H) 7.30 (s, 1H) 7.50 (t, J=7.58Hz, 1H) 7.72-7.82 (m, 1H) 7.99 (t, J=9.09 Hz, 2H) 8.11 (dd, J=8.34, 1.77Hz, 1H) 8.17 (s, 1H) 8.88 (d, J=1.52 Hz, 1H); ESI-MS: m/z calc'd forC₁₉H₁₄N₄O₃S 378.08. found 379.2 (M+H)⁺.

Example 11(Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide

Commercially available 4-aminothiophenol (Aldrich) (0.5 g, 4 mmol) andTEA (0.56 mL, 4 mmol) was stirred in THF (4 mL) at 0° C. A solution ofcyclopropanecarbonyl chloride (0.37 mL, 4 mol) in THF (2 mL) was addeddrop wise to the above mixture, and the mixture was stirred at 0° C. for0.5-1 hr. The solid was filtered off and the filtrate diluted with EtOAcand washed with saturated HCO₃ ⁻. The aqueous layer was acidified withconc. HCl and extracted with EtOAc. The organic phase was washed withbrine, dried over anhydrous MgSO₄, and concentrated to get a solid.

Then, Example 11 was synthesized using the above material and(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one(Example 1) according to the procedure described in the synthesis ofExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 0.85 (d, J=5.31 Hz, 4H)1.83-1.85 (m, 1H) 1.96 (s, 3H) 6.79 (s, 1H) 7.67-7.69 (m, 3H) 7.87 (d,J=7.83 Hz, 2H) 7.92-7.94 (m, 1H) 8.03 (d, J=8.34 Hz, 1H) 8.19 (d, J=8.34Hz, 1H) 10.63 (s, 1H); ESI-MS: m/z calc'd for C₂₃H₂₀N₄O₂S 416.13. found417.3 (M+H)⁺.

Example 12(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-ethyl-1H-pyrazol-5(4H)-one

The title compound was synthesized using 4-chloroquinoline N-oxide andmethyl 3-oxo-pentanoate following the procedure described in thesynthesis of Example 1, with the exception that a 10:3 ratio of ethanolto acetic acid was used for the cyclization of pyrrazole. ¹H NMR (400MHz, DMSO-D6) δ ppm 1.25 (t, J=7.45 Hz, 3H) 3.06 (d, J=1.01 Hz, 2H) 7.61(t, J=7.58 Hz, 1H) 7.79 (t, J=7.58 Hz, 1H) 7.94 (d, J=8.34 Hz, 1H) 8.09(d, J=8.08 Hz, 2H) 12.03 (s, 1H); ESI-MS: m/z calc'd for C₁₄H₁₂ClN₃O273.07. found 274.2 (M+H)⁺.

Example 13(Z)—N-(4-(2-(3-ethyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-ethyl-1H-pyrazol-5(4H)-one and4-acetamidothiophenol using the procedure described in Example 6. ¹H NMR(400 MHz, DMSO-D6) δ ppm 0.82 (t, J=7.45 Hz, 3H) 2.06-2.16 (s, 3H)2.17-2.25 (m, 2H) 6.63 (s, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.67 (d, J=8.59Hz, 2H) 7.78-7.89 (m, 4H) 8.08 (d, J=8.34 Hz, 1H) 10.32 (s, 1H); ESI-MS:m/z calc'd for C₂₂H₂₀N₄O₂S 404.13. found 405.2 (M+H)⁺.

Example 14(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

Example 15(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one

3-Cyclopropyl-3-oxo-propionic acid (0.5 g, 3.2 mmol) was stirred inethanol and acetic acid (10:1, 2.2 mL) and treated with hydrazine (0.12mL, 3.8 mmol). After 15 hrs, the solid was filtered off and washed witha minimum amount of ethanol. Then, the product(3-cyclopropyl-1H-pyrazol-5(4H)-one) (0.4 mmol) and 4-chloroquinolineN-oxide (0.087 g, 0.48 mmol) were stirred in acetic anhydride (1 mL) atambient temperature for 20-30 minutes. The reaction mixture wasconcentrated and carried out to the next step with out any purification.The resulting(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-onewas dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.076 g,0.45 mmol) was added. The reaction mixture was heated to 180° C. using amicrowave reactor for 30 minutes. The mixture was concentrated andpurified by LC-MS to give the title compounds of Example 14 and Example15.

Example 14

¹H NMR (400 MHz, DMSO-D6) δ ppm 0.30-0.37 (m, 2H) 0.55-0.61 (m, 2H)1.26-1.35 (m, 1H) 2.07 (s, 3H) 7.10 (s, 1H) 7.60 (t, J=7.58 Hz, 1H) 7.69(d, J=8.34 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H) 7.84 (t, J=7.71 Hz, 1H)7.88-7.92 (m, 1H) 8.12 (d, J=8.08 Hz, 1H) 10.30 (s, 1H); ESI-MS: m/zcalc'd for C₂₃H₂₀N₄O₂S 416.13. found 417.2 (M+H)⁺.

Example 15

¹H NMR (400 MHz, DMSO-D6) δ ppm 0.47-0.55 (m, 2H) 0.59-0.65 (m, 2H)1.30-1.41 (m, 1H) 6.73 (d, J=8.34 Hz, 2H) 7.15 (s, 1H) 7.32 (d, J=8.34Hz, 2H) 7.54-7.60 (m, 1H) 7.83-7.90 (m, 2H) 8.09 (d, J=8.34 Hz, 1H);ESI-MS: m/z calc'd for C₂₁H₁₈N₄OS 374.12. found 375.2 (M+H)⁺.

Example 16(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-oneand N-(4-mercaptophenyl)cyclopropanecarboxamide under conditions similarto those described in Example 6. The final compound was purified byprecipitating it from methanol. ¹H NMR (400 MHz, DMSO-D6) δ ppm0.17-0.29 (m, 2H) 0.47-0.59 (m, 2H) 0.77-0.87 (m, 4H) 1.05-1.17 (m, 1H)1.74-1.84 (m, 1H) 6.96 (s, 1H) 7.49-7.60 (m, 1H) 7.68 (d, J=8.59 Hz, 2H)7.77-7.81 (m, 4H) 8.06 (d, J=7.07 Hz, 1H) 10.52 (s, 1H) 11.03 (s, 1H)11.82 (s, 1H); ESI-MS: m/z calc'd for C₂₅H₂₂N₄O₂S 442.15. found 443.3(M+H)⁺.

Example 17(Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was synthesized according to the procedure describedin Example 6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H) 7.41 (dd,J=7.20, 4.93 Hz, 1H) 7.56 (t, J=7.58 Hz, 2H) 7.78-7.88 (m, 3H) 7.97 (d,J=8.59 Hz, 1H) 8.07 (d, J=8.08 Hz, 1H) 8.59 (d, J=3.79 Hz, 1H); ESI-MS:m/z calc'd for C₁₈H₁₄N₄OS 334.39. found 335.2 (M+H)⁺.

Example 18(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one

Methyl isobutyrylacetate (0.5 g, 3.47 mmol) was stirred in ethanol andacetic acid (10:1, 2:0.2 mL) and treated with hydrazine (0.13 mL, 4.16mmol). After 24 hrs, the resulting solid was filtered off and washedwith a minimum amount of ethanol to yield3-isopropyl-1H-pyrazol-5(4H)-one. Then, the3-isopropyl-1H-pyrazol-5(4H)-one (0.169 g, 1.34 mmol) and4-chloroquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in aceticanhydride (1.5 mL) at ambient temperature for 20-30 minutes. Thereaction mixture was concentrated and the resulting solid was filteredoff and washed with a minimum amount of ether to yield Example 18. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.30 (d, J=6.82 Hz, 6H) 3.98 (bs, 1H) 7.61(t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18(m, 2H); ESI-MS: m/z calc'd for C₁₅H₁₄ClN₃O 287.74. found 288.2 (M+H)⁺.

Example 19(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one(0.029 g, 0.089 mmol) was dissolved in ethanol (1 mL) and4-acetamidothiophenol (0.016 g, 0.094 mmol) was added. The reactionmixture was heated to 180° C. using a microwave reactor for 30 minutes.The mixture was then concentrated and purified by LC-MS to give Example19. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96 (d, J=6.82 Hz, 6H) 2.13 (s, 3H)2.53 (bs, 1H) 6.65 (s, 1H) 7.68-7.70 (m, 3H) 7.86-7.97 (m, 3H) 8.02 (s,1H) 8.20 (d, J=8.34 Hz, 1H) 10.43 (s, 1H); ESI-MS: m/z calc'd forC₂₃H₂₂N₄O₂S 418.51. found 419.3 (M+H)⁺.

Example 20(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one

Example 20 was synthesized from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-oneand 4-aminothiophenol according to the procedure described in Example19. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (bs, 6H) 3.33 (bs, 1H) 5.87 (s,1H) 6.78 (d, J=8.34 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H) 7.52 (bs, 1H) 7.77(bs, 1H) 8.03 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C₂₁H₂₀N₄OS376.47. found 377.2 (M+H)⁺.

Example 21(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one(0.8 g, 2.78 mmol) was stirred in DMF at ambient temperature andDi-t-butyl dicarbonate (3 g, 13.9 mmol) was added followed bytriethylamine (1.9 mL, 13.9 mmol). After 24 hrs, the reaction mixturewas diluted with EtOAc and worked up with DI water. The organic phasewas washed with brine, dried over MgSO₄, and concentrated to dryness andpurified by LC-MS. The resulting (Z)-tert-butyl2-(1-(tert-butoxycarbonyl)-3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-4-chloroquinoline-1(2H)-carboxylate(0.072 g, 0.14 mmol) was stirred in ethanol and 4-aminothiophenol wasadded. The reaction mixture was heated at 30° C. for 4 hrs, concentratedto dryness, and carried out to the next step without furtherpurification. The resulting (Z)-tert-butyl4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylatewas dissolved in pyridine (1-2 mL) and treated with methanesulfonylchloride (0.035 mL, 0.44 mmol). After 1 hr, the solvent was evaporatedand the solid redissolved in dichloromethane. Trifluoroacetic acid (0.9mL) was added dropwise. The final compound was purified by LC-MS toyield Example 21. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (d, J=6.82 Hz,6H) 2.58 (bs, 1H) 3.17 (s, 3H) 6.69 (s, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.63(t, J=7.58 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H) 7.83-7.94 (m, 2H) 8.13 (d,J=8.34 Hz, 1H) 10.40 (s, 1H); ESI-MS: m/z calc'd for C₂₂H₂₂N₄O₃S₂454.57. found 455.2 (M+H)⁺.

Example 22(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide

Example 22 was synthesized from (Z)-tert-butyl4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylateand ethanesulfonyl chloride according to the procedure described inExample 21. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (d, J=6.82 Hz, 6H) 1.27(t, J=7.33 Hz, 3H) 2.57 (bs, 1H) 3.27 (q, J=7.33 Hz, 2H) 7.30 (d, J=8.34Hz, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.59-7.65 (m, 1H) 7.71 (d, J=8.59 Hz,2H) 7.85-7.91 (m, 2H) 8.13 (d, J=8.34 Hz, 1H) 10.41 (s, 1H); ESI-MS: m/zcalc'd for C₂₃H₂₄N₄O₃S₂ 468.59. found 469.2 (M+H)⁺.

Example 23(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one

Methyl butyrylacetate (4 g, 27.7 mmol) was stirred in ethanol and aceticacid (10:1, 8:0.8 mL) and treated with hydrazine (1.05 mL, 33.3 mmol).After 2 hrs, the resulting solid was filtered off and washed with aminimum amount of acetonitrile to yield 3-propyl-1H-pyrazol-5(4H)-one.Then, the 3-propyl-1H-pyrazol-5(4H)-one (4.68 g, 11.8 mmol) and4-chloroquinoline N-oxide (1.5 g, 11.8 mmol) were stirred in aceticanhydride (20 mL) at ambient temperature for 30-40 minutes. The reactionmixture was concentrated, and the resulting solid filtered off, washedwith a minimum amount of methanol, and treated with hydrazine (0.84 mL,26.7 mmol) in methanol (12 mL) to yield Example 23 as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.97 (t, J=7.33 Hz, 3H) 1.66-1.76 (m, 2H) 3.02(t, J=7.07 Hz, 2H) 7.62 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93(d, J=8.34 Hz, 1H) 8.10 (d, J=8.34 Hz, 2H); ESI-MS: m/z calc'd forC₁₅H₁₄ClN₃O 287.74. found 288.2 (M+H)⁺.

Example 24(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one(0.045 g, 0.013 mmol) was dissolved in ethanol (1.5 mL) and4-acetamidothiophenol (0.023 g, 0.013 mmol) was added. The reactionmixture was heated to 180° C. using a microwave reactor for 5-10minutes. The mixture was then concentrated and the resulting solidfiltered and washed with ether. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t,J=7.33 Hz, 3H) 1.32 (qd, J=7.45, 7.20 Hz, 2H) 2.11 (s, 3H) 2.25 (t,J=7.07 Hz, 2H) 6.76 (s, 1H) 7.63-7.71 (m, 3H) 7.89 (t, J=8.84 Hz, 3H)7.93-7.99 (m, 1H) 8.17 (d, J=8.34 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/zcalc'd for C₂₃H₂₂N₄O₂S 418.51. found 419.3 (M+H)⁺.

Example 25(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one(0.045 g, 0.013 mmol) was dissolved in ethanol (1.5 mL) and4-aminothiophenol (0.017 g, 0.013 mmol) was added. The reaction mixturewas heated to 180° C. using a microwave reactor for 5-10 minutes. Themixture was then concentrated and purified by LC-MS to give Example 25.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78 (t, J=7.45 Hz, 3H) 1.30-1.40 (m,2H) 2.22-2.32 (m, 2H) 6.77 (d, J=8.34 Hz, 3H) 7.33 (d, J=8.59 Hz, 2H)7.60 (t, J=7.33 Hz, 1H) 7.82-7.92 (m, 2H) 8.12 (d, J=8.08 Hz, 1H);ESI-MS: m/z calc'd for C₂₁H₂₀N₄OS 376.47. found 377.2 (M+H)⁺.

Example 26(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one(1.0 g, 3.48 mmol) was stirred in DMF at ambient temperature andDi-t-butyl dicarbonate (2.28 g, 10.5 mmol) was added followed bytriethylamine (2.43 mL, 17.4 mmol). After 24 hrs, the reaction mixturewas diluted with EtOAc and worked up with DI water. The organic phasewas washed with brine and dried over MgSO₄, and concentrated to drynessand triturated with methanol. The resulting (Z)-tert-butyl2-(1-(tert-butoxycarbonyl)-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-4-chloroquinoline-1(2H)-carboxylate (0.1 g, 0.21 mmol) was stirred in ethanol and4-aminothiophenol (0.031 g, 0.25 mmol) was added. The reaction mixturewas heated at 30° C. for 2 hrs, concentrated to dryness, and carried outto the next step without further purification. The resulting(Z)-tert-butyl4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylatewas dissolved in pyridine (1-2 mL) and treated with methanesulfonylchloride (0.048 mL, 0.61 mmol). After 2-4 hr, the solvent was evaporatedand the solid redissolved in dichloromethane. Trifluoroacetic acid (1.2mL) was added dropwise. The final compound was purified by LC-MS toyield Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73 (t, J=7.33 Hz,3H) 1.27-1.37 (m, 2H) 2.30 (t, J=7.33 Hz, 2H) 3.14 (s, 3H) 6.80 (s, 1H)7.43 (d, J=8.59 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.72 (d, J=8.59 Hz, 2H)7.84-7.95 (m, 2H) 8.14 (d, J=8.08 Hz, 1H) 10.34 (s, 1H); ESI-MS: m/zcalc'd for C₂₂H₂₂N₀O₃S₂ 454.57. found 455.2 (M+H)⁺.

Example 27(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand ethanesulfonyl chloride according to the procedure described in thesynthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (t, J=7.45Hz, 3H) 1.33 (t, J=7.33 Hz, 3H) 1.56 (dq, J=15.00, 7.46 Hz, 2H)2.77-2.83 (m, 2H) 3.49-3.51 (m, 2H) 6.72 (d, J=8.59 Hz, 2H) 7.29 (d,J=8.34 Hz, 2H) 7.63 (t, J=7.58 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.94 (d,J=8.34 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H) 12.92 (s, 1H); ESI-MS: m/z calc'dfor C₂₃H₂₄N₄O₃S₂ 468.59. found 469.2 (M+H)⁺.

Example 28(Z)-2-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 2-(dimethylamino)acetyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.71 (t, J=7.33 Hz, 3H) 1.28-1.38 (m, 2H) 2.24 (bs, 2H) 2.90 (s, 6H)4.21 (s, 2H) 6.79 (s, 1H) 7.58 (t, J=7.58 Hz, 1H) 7.76 (d, J=8.59 Hz,2H) 7.79-7.90 (m, 4H) 8.10 (d, J=8.34 Hz, 1H) 9.89 (s, 1H) 10.94 (s,1H); ESI-MS: m/z calc'd for C₂₅H₂₇N₅O₂S 461.58. found 462.3 (M+H)⁺.

Example 29(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)benzamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand benzoyl chloride in THF according to the procedure described in thesynthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71 (t, J=7.33Hz, 3H) 1.29-1.39 (m, 2H) 2.26 (t, J=6.82 Hz, 2H) 6.80 (s, 1H) 7.55-7.67(m, 4H) 7.76 (d, J=8.59 Hz, 2H) 7.85-7.94 (m, 2H) 7.98 (d, J=7.07 Hz,2H) 8.11 (d, J=8.59 Hz, 2H) 8.17 (d, J=8.08 Hz, 1H) 10.62 (s, 1H);ESI-MS: m/z calc'd for C₂₈H₂₄N₄O₂S 480.58. found 481.2 (M+H)⁺.

Example 30(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclobutanecarboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand cyclobutanecarbonyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.68 (t, J=7.33 Hz, 3H) 1.30 (qd, J=7.49, 7.33 Hz, 2H) 1.78-1.89 (m,1H) 1.91-2.03 (m, 1H) 2.12-2.16 (m, 2H) 2.18-2.27 (m, 5H) 6.73 (s, 1H)7.60-7.70 (m, 3H) 7.83-7.94 (m, 4H) 8.14 (d, J=8.08 Hz, 1H) 10.11 (s,1H); ESI-MS: m/z calc'd for C₂₆H₂₆N₄O₂S 458.58. found 459.3 (M+H)⁺.

Example 31(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopentanecarboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand cyclopentanecarbonyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.97, 7.39 Hz, 2H) 1.54-1.63(m, 2H) 1.65-1.77 (m, 4H) 1.82-1.92 (m, 2H) 2.20 (t, J=7.33 Hz, 2H) 2.83(dt, J=15.41, 7.71 Hz, 1H) 6.73 (s, 1H) 7.59-7.70 (m, 3H) 7.83-7.94 (m,4H) 8.13 (d, J=8.08 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd forC₂₇H₂₈N₄O₂S 472.6. found 473.3 (M+H)⁺.

Example 32(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)furan-2-carboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 2-furoyl chloride in THF according to the procedure described in thesynthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.68 (t, J=7.33Hz, 3H) 1.25-1.36 (m, J=7.39, 7.39, 7.39, 7.39 Hz, 2H) 2.25 (t, J=6.69Hz, 2H) 6.73-6.83 (m, 2H) 7.41 (d, J=3.28 Hz, 1H) 7.63 (t, J=7.58 Hz,1H) 7.74 (d, J=8.59 Hz, 2H) 7.83-7.95 (m, 2H) 8.00 (s, 1H) 8.08 (d,J=8.59 Hz, 2H) 8.15 (d, J=8.08 Hz, 1H) 10.55 (s, 1H); ESI-MS: m/z calc'dfor C₂₆H₂₂N₄O₃S 470.54. found 471.3 (M+H)⁺.

Example 33(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)thiophene-2-carboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 2-thiophene carbonyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.69 (t, J=7.33 Hz, 3H) 1.28-1.37 (m, 2H) 2.26 (t, J=7.20 Hz, 2H)6.80 (s, 1H) 7.27 (t, J=4.29 Hz, 1H) 7.63 (t, J=7.58 Hz, 1H) 7.75 (d,J=8.34 Hz, 2H) 7.86 (t, J=7.58 Hz, 1H) 7.92 (d, J=5.05 Hz, 2H) 8.05 (d,J=8.59 Hz, 2H) 8.08 (d, J=3.79 Hz, 1H) 8.15 (d, J=8.08 Hz, 1H) 10.56 (s,1H); ESI-MS: m/z calc'd for C₂₆H₂₂N₄O₂S₂ 486.61. found 487.2 (M+H)⁺.

Example 34(Z)-2-methoxy-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand methoxy acetyl chloride in THF according to the procedure describedin the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (t,J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.23(t, J=7.33 Hz, 2H) 3.40 (s, 3H) 4.06 (s, 2H) 6.76 (s, 1H) 7.64 (t,J=7.71 Hz, 1H) 7.70 (d, J=8.34 Hz, 2H) 7.87 (t, J=7.71 Hz, 1H) 7.91-7.96(m, 1H) 7.98 (d, J=8.59 Hz, 2H) 8.15 (d, J=8.34 Hz, 1H) 10.18 (s, 1H);ESI-MS: m/z calc'd for C₂₄H₂₄N₄O₃S 448.54. found 449.2 (M+H)⁺.

Example 35(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propionamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand propionyl chloride in THF according to the procedure described inthe synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t,J=7.33 Hz, 3H) 1.11 (t, J=7.58 Hz, 3H) 1.27-1.37 (m, J=14.87, 7.41,7.41, 7.20 Hz, 2H) 2.22 (t, J=6.95 Hz, 2H) 2.38 (q, J=7.41 Hz, 2H) 6.74(s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.83-7.93 (m,4H) 8.13 (d, J=8.34 Hz, 1H) 10.26 (s, 1H); ESI-MS: m/z calc'd forC₂₄H₂₄N₄O₂S 432.54. found 433.2 (M+H)⁺.

Example 36(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butyramide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand butyryl chloride in THF according to the procedure described in thesynthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (t, J=7.33Hz, 3H) 0.94 (t, J=7.33 Hz, 3H) 1.26-1.35 (m, J=7.36, 7.36, 7.36, 7.36,7.20 Hz, 2H) 1.59-1.69 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.21(t, J=7.20 Hz, 2H) 2.34 (t, J=7.20 Hz, 2H) 6.74 (s, 1H) 7.62 (t, J=7.71Hz, 1H) 7.68 (d, J=8.59 Hz, 2H) 7.83-7.93 (m, 4H) 8.13 (d, J=8.34 Hz,1H) 10.26 (s, 1H); ESI-MS: m/z calc'd for C₂₅H₂₆N₄O₂S 446.56. found447.3 (M+H)⁺.

Example 37(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand cyclopropanecarboxylic acid chloride in THF according to theprocedure described in the synthesis of Example 26. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.70 (t, J=7.33 Hz, 3H) 0.82-0.88 (m, 4H) 1.27-1.37 (m,J=7.45, 7.45, 7.45, 7.45, 7.33 Hz, 2H) 1.83 (dq, J=6.32, 6.15 Hz, 1H)2.23 (t, J=7.33 Hz, 2H) 6.75 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d,J=8.59 Hz, 2H) 7.88 (td, J=13.64, 7.83 Hz, 4H) 8.14 (d, J=8.08 Hz, 1H)10.58 (s, 1H); ESI-MS: m/z calc'd for C₂₅H₂₄N₄O₂S 444.55. found 445.3(M+H)⁺.

Example 38 (Z)-2-methoxyethyl4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenylcarbamate

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand chloroformic acid 2-methoxy ethyl ester in THF according to theprocedure described in the synthesis of Example 26. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.70 (t, J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.45, 7.45, 7.45,7.45, 7.33 Hz, 2H) 2.22 (t, J=7.07 Hz, 2H) 3.27-3.32 (m, 2H) 3.57-3.61(m, 2H) 4.22-4.28 (m, 2H) 6.74 (s, 1H) 7.59-7.70 (m, 3H) 7.72-7.78 (m,2H) 7.83-7.94 (m, 2H) 8.13 (d, J=8.08 Hz, 1H) 10.21 (s, 1H); ESI-MS: m/zcalc'd for C₂₅H₂₆N₄O₄S 478.56. found 479.2 (M+H)⁺.

Example 39(Z)-3-(methylthio)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 3-methylthiopropionyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.69 (t, J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.36, 7.36, 7.36, 7.36, 7.20Hz, 2H) 2.11 (s, 3H) 2.17-2.27 (m, 2H) 2.68 (t, J=6.82 Hz, 2H) 2.78 (t,J=6.95 Hz, 2H) 6.75 (s, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.66-7.72 (m, 2H)7.82-7.92 (m, 4H) 8.12 (d, J=8.08 Hz, 1H) 10.36 (s, 1H); ESI-MS: m/zcalc'd for C₂₅H₂₆N₄O₂S₂ 478.63. found 479.2 (M+H)⁺.

Example 40(Z)-4-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butanamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 4-(dimethylamino)butanoyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.70 (t, J=7.33 Hz, 3H) 1.27-1.38 (m, J=7.45, 7.45, 7.45, 7.45 Hz,2H) 1.90-1.99 (m, 2H) 2.21 (m, 2H) 2.44-2.49 (m, 2H) 2.81 (d, J=4.80 Hz,6H) 3.07-3.15 (m, 2H) 6.76 (s, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.69 (d,J=8.34 Hz, 2H) 7.79-7.90 (m, 4H) 8.09 (d, J=8.34 Hz, 1H) 9.43 (s, 1H)10.40 (s, 1H); ESI-MS: m/z calc'd for C₂₇H₃₁N₅O₂S 489.63. found 490.3(M+H)⁺.

Example 41(Z)-3-(diethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 3-(diethylamino)propanoyl chloride in THF according to the proceduredescribed in the synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.71 (t, J=7.45 Hz, 3H) 1.23 (t, J=7.20 Hz, 6H) 1.28-1.37 (m, 2H)2.19-2.29 (m, 2H) 2.88 (t, J=7.07 Hz, 2H) 3.18 (ddd, J=12.69, 6.82, 6.51Hz, 4H) 3.38-3.42 (m, 2H) 6.78 (s, 1H) 7.54-7.62 (m, 1H) 7.71 (d, J=8.59Hz, 2H) 7.79-7.90 (m, 4H) 8.09 (d, J=8.34 Hz, 1H) 9.12 (s, 1H) 10.57 (s,1H); ESI-MS: m/z calc'd for C₂₈H₃₃N₅O₂S 503.66. found 504.2 (M+H)⁺.

Example 42(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)isobutyramide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand isobutyryl chloride in THF according to the procedure described inthe synthesis of Example 26. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (t,J=7.33 Hz, 3H) 1.13 (d, J=6.82 Hz, 6H) 1.27-1.37 (m, J=7.42, 7.42, 7.42,7.42, 7.20 Hz, 2H) 2.20 (t, J=7.20 Hz, 2H) 2.65 (dt, J=13.58, 6.73 Hz,1H) 6.73 (s, 1H) 7.62 (t, J=7.58 Hz, 1H) 7.68 (d, J=8.34 Hz, 2H)7.83-7.93 (m, 4H) 8.13 (d, J=8.08 Hz, 1H) 10.22 (s, 1H); ESI-MS: m/zcalc'd for C₂₅H₂₆N₄O₂S 446.56. found 447.1 (M+H)⁺.

Example 43(R,Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)pyrrolidine-2-carboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand (R)-1-methylpyrrolidine-2-carbonyl chloride in THF according to theprocedure described in the synthesis of Example 26. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.30-1.40 (m, J=7.45, 7.45, 7.45,7.45 Hz, 2H) 1.94-2.04 (m, 2H) 2.10-2.23 (m, 3H) 2.60-2.63 (m, 1H) 2.91(s, 3H) 3.24-3.27 (m, 1H) 4.21-4.30 (m, 1H) 6.79 (s, 1H) 7.57 (t, J=7.71Hz, 1H) 7.75-7.83 (m, 3H) 7.85-7.90 (m, 3H) 8.09 (d, J=8.08 Hz, 1H) 9.87(s, 1H) 11.01 (s, 1H); ESI-MS: m/z calc'd for C₂₇H₂₉N₅O₂S 487.62. found488.1 (M+H)⁺.

Example 44(Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)piperidine-4-carboxamide

The title compound was synthesized using(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-oneand 1-methylpiperidine-4-carbonyl chloride in THF according to theprocedure described in the synthesis of Example 26. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.84, 7.35 Hz, 2H)1.79-1.90 (m, 2H) 2.02-2.05 (m, 2H) 2.16-2.18 (m, 2H) 2.58-2.69 (m, 2H)2.79-2.84 (m, 3H) 2.94-3.06 (m, 2H) 6.73 (s, 1H) 7.57 (t, J=7.45 Hz, 1H)7.69 (d, J=8.59 Hz, 2H) 7.79-7.91 (m, 4H) 8.09 (d, J=8.08 Hz, 1H) 9.28(s, 1H) 10.45 (s, 1H); ESI-MS: m/z calc'd for C₂₈H₃₁N₅O₂S 501.64. found502.1 (M+H)⁺.

Example 45(Z)—N-(4-(6-methoxy-2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

3-Propyl-1H-pyrazol-5(4H)-one (1.16 mmol) and4-chloro-6-methoxyquinoline 1-oxide (0.15 g, 1.16 mmol) were stirred inacetic anhydride (3 mL) at ambient temperature for 30-40 minutes. Thereaction mixture was concentrated and the resulting solid was filteredoff and washed with a minimum amount of ether.(Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one(0.06 g, 0.016 mmol) was dissolved in ethanol (1.5 mL) and4-acetamidothiophenol (0.028 g, 0.016 mmol) was added. The reactionmixture was heated to 180° C. using a microwave reactor for 5-10minutes. The mixture was then concentrated and the resulting solidfiltered and washed with ether to give Example 45. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.27-1.37 (m, J=7.48, 7.48, 7.48,7.48, 7.48 Hz, 2H) 2.11 (s, 3H) 2.31 (t, J=7.45 Hz, 2H) 3.96 (s, 3H)6.83 (s, 1H) 7.42 (d, J=2.78 Hz, 1H) 7.57 (dd, J=9.09, 2.27 Hz, 1H) 7.68(d, J=8.59 Hz, 2H) 7.87 (d, J=8.59 Hz, 2H) 8.00 (d, J=9.35 Hz, 1H) 10.36(s, 1H); ESI-MS: m/z calc'd for C₂₄H₂₄N₄O₃S 448.54. found 449.2 (M+H)⁺.

Example 46(Z)-4-(4-(4-aminophenylthio)-6-methoxyquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one

Example 46 was synthesized according to a procedure analogous to thatdescribed in Example 45. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77 (t, J=7.45Hz, 3H) 1.35 (dq, J=14.68, 7.40 Hz, 2H) 2.26-2.37 (m, 2H) 3.92 (s, 3H)5.80 (s, 1H) 6.75 (d, J=8.59 Hz, 2H) 7.30-7.35 (m, 3H) 7.44 (dd, J=9.22,2.65 Hz, 1H) 7.83 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C₂₂H₂₂N₄O₂S406.5. found 407.2 (M+H)⁺.

Example 47(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-6-methoxy-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.2 mmol) and4-chloro-6-methoxyquinoline 1-oxide (0.025 g, 0.2 mmol) were stirred inacetic anhydride (1.5 mL) at ambient temperature for 30-40 minutes. Thereaction mixture was concentrated and the resulting solid filtered offand washed with a minimum amount of ether.(Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one(0.04 g, 0.11 mmol) was dissolved in ethanol (1.5 mL) and4-acetamidothiophenol (0.019 g, 0.11 mmol) was added. The reactionmixture was heated to 180° C. using a microwave reactor for 5-10minutes. The mixture was then concentrated and the resulting solidfiltered and washed with ether to give Example 47. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.46 (d, J=6.57 Hz, 2H) 0.65-0.71 (m, 2H) 1.43-1.54 (m,1H) 2.11 (s, 3H) 3.98 (s, 3H) 7.18 (s, 1H) 7.45 (d, J=2.53 Hz, 1H) 7.63(dd, J=9.09, 2.27 Hz, 1H) 7.70 (d, J=8.59 Hz, 2H) 7.82 (d, J=8.59 Hz,2H) 8.07 (d, J=9.09 Hz, 1H) 10.39 (s, 1H); ESI-MS: m/z calc'd forC₂₄H₂₂N₄O₃S 446.52. found 447.2 (M+H)⁺.

Example 48(Z)—N-(4-(2-(3-cyclohexyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

3-Cyclohexyl-3-oxo-propionic acid ethyl ester (0.5 g, 2.52 mmol) wasstirred in ethanol and acetic acid (10:1, 2:0.2 mL), and treated withhydrazine (0.095 mL, 3.03 mmol). After 18 hrs, the resulting solid wasfiltered off and washed with a minimum amount of ethanol to yield3-cyclohexyl-1H-pyrazol-5(4H)-one. Then, the3-cyclohexyl-1H-pyrazol-5(4H)-one (0.2 g, 1.23 mmol) and4-chloroquinoline N-oxide (1.23 mmol) were stirred in acetic anhydride(20 mL) at ambient temperature for 60-90 minutes. The reaction mixturewas concentrated and the resulting solid filtered off and washed with aminimum amount of ether.(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one(0.05 g, 0.13 mmol) was dissolved in ethanol (1.5 mL) and4-acetamidothiophenol (0.023 g, 0.13 mmol) was added. The reactionmixture was heated to 180° C. using a microwave reactor for 5-10minutes. The solid was filtered and washed with ethanol to yield Example48. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88-1.00 (m, 2H) 1.26-1.38 (m, 2H)1.58 (d, J=10.61 Hz, 6H) 2.10 (s, 3H) 2.33 (t, J=9.47 Hz, 1H) 6.87 (s,1H) 7.62-7.72 (m, 3H) 7.89 (t, J=7.83 Hz, 4H) 8.17 (d, J=8.34 Hz, 1H)10.37 (s, 1H); ESI-MS: m/z calc'd for C₂₆H₂₆N₄O₂S 458.58. found 459.1(M+H)⁺.

Example 49(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-oneand 4-aminothiophenol using the procedure described in Example 48. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.19 (m, 3H) 1.29-1.40 (m, 2H)1.58-1.65 (m, 4H) 1.67 (d, J=9.60 Hz, 2H) 2.37 (t, J=10.23 Hz, 1H) 6.76(d, J=8.59 Hz, 2H) 6.90 (s, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (t, J=7.33Hz, 1H) 7.85-7.93 (m, 2H) 8.16 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'dfor C₂₄H₂₄N₄OS 416.54. found m/z 417.1 (M+H)⁺.

Example 50(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylsulfonyl)phenyl)propionamide

(Z)-tert-butyl4-(4-acetamidophenylthio)-2-(1-(tert-butoxycarbonyl)-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylate(0.17 mmol) and 4-methyl morpholine N-oxide monohydrate (0.52 mmol) werestirred in acetone/water (0.34 m/0.16 mL), and treated with osmiumtetraoxide (0.017 mmol). After 48 hrs, the reaction mixture was quenchedwith saturated Na₂S₂O₃ and worked up with ethyl acetate. The organicphase was washed with brine, dried over MgSO₄, and concentrated todryness. The resulting residue was redissolved in dichloromethane andtreated with trifluoroacetic acid (1.2 mL). The final compound waspurified by LC-MS to yield Example 50. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.97 (t, J=7.33 Hz, 3H) 1.04 (t, J=7.45 Hz, 3H) 1.65-1.75 (m, 2H) 2.33(q, J=7.58 Hz, 2H) 2.98-3.05 (m, 2H) 7.57 (t, J=7.58 Hz, 1H) 7.74-7.84(m, 3H) 7.96 (d, J=8.84 Hz, 3H) 8.38 (d, J=8.34 Hz, 1H) 8.78 (s, 1H)10.35 (s, 1H); ESI-MS: m/z calc'd for C₂₄H₂₄N₄O₄S 464.54. found 465.3(M+H)⁺.

Example 51(Z)-5-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylamino)-1H-indazol-3(2H)-one

(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one(0.03 g, 0.1 mmol) was dissolved in ethanol (1.5 mL) and di-tert-butyl5-amino-3-oxo-1H-indazole-1,2(3H)-dicarboxylate (0.044 g, 0.12 mmol) wasadded. The reaction mixture was heated to 170° C. using a microwavereactor for 30 minutes. The mixture was concentrated and purified byLC-MS to give the title compound of Example 51. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.51 (t, J=6.95 Hz, 3H) 1.26-1.33 (m, 2H) 2.39 (dd,J=9.09, 3.28 Hz, 2H) 6.41 (s, 1H) 7.38 (dd, J=8.72, 1.64 Hz, 1H)7.45-7.51 (m, 1H) 7.67-7.73 (m, 2H) 7.90-7.98 (m, 2H) 8.59 (d, J=7.58Hz, 1H) 10.49 (s, 1H) 11.79 (s, 1H); ESI-MS: m/z calc'd for C₂₂H₂₀N₆O₂400.43. found 401.3 (M+H)⁺.

Example 52(Z)—N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide

The tile compound was synthesized usingN-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamideand quinoline N-oxide in acetic anhydride according to the proceduredescribed in Example 23. TheN-(4-((5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamidewas synthesized using 2-(4-(methylsulfonamido)phenyl)acetic acid andMeldrum's acid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.91 (s, 3H) 4.08 (s,1H) 4.43 (s, 1H) 7.10 (d, J=3.79 Hz, 2H) 7.24-7.37 (m, 2H) 7.46 (d,J=6.06 Hz, 1H) 7.67-7.77 (m, 2H) 7.82-7.94 (m, 2H) 8.17-8.29 (m, 1H)9.60 (s, 1H) 11.40 (s, 1H); ESI-MS: m/z calc'd for C₂₀H₁₈N₄O₃S 394.45.found 395.3 (M+H)⁺.

Example 53 (Z)-3-phenyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was synthesized using 3-phenyl-1H-pyrazol-5(4H)-oneand quinoline N-oxide according to the procedure described in Example23. ¹H NMR (400 MHz, DMSO-d₆) 8 ppm 7.21 (d, J=9.09 Hz, 1H) 7.50-7.60(m, 7H) 7.82 (t, J=7.71 Hz, 1H) 7.93 (t, J=6.82 Hz, 2H) 8.33 (d, J=8.84Hz, 1H); ESI-MS: m/z calc'd for C₁₈H₁₃N₃O 287.32. found 288.3 (M+H)⁺.

Example 54(Z)—N-methyl-4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide

The title compound was synthesized usingN-methyl-4-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide andquinoline N-oxide according to the procedure described in Example 23. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.49 (s, 3H) 7.09 (s, 1H) 7.48-7.60 (m, 2H)7.76-7.81 (m, 3H) 7.83-7.90 (m, 4H) 8.25 (d, J=9.09 Hz, 2H) 11.90 (s,1H); ESI-MS: m/z calc'd for C₁₉H₁₆N₄O₃S 380.42. found 381.2 (M+H)⁺.

Example 55 (Z)-3-cyclopropyl-4-(isoquinolin-1(2H)-ylidene)-1H-pyrazol-5(4H)-one

3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.03 g, 0.27 mmol) and isoquinolineN-oxide (0.04 g, 0.27 mmol) were stirred in acetic anhydride (0.5 mL)for 30-40 minutes. The reaction mixture was concentrated and purified byLC-MS to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.78-0.86 (m, 4H) 1.77-1.86 (m, 1H) 7.91 (t, J=7.71 Hz, 1H) 8.10 (t,J=7.58 Hz, 1H) 8.26 (d, J=8.59 Hz, 3H) 8.58 (d, J=6.57 Hz, 1H); ESI-MS:m/z calc'd for C₁₅H₁₃N₃O 251.28. found 252.2 (M+H)⁺.

Example 56(Z)—N-(4-(2-(1-methyl-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

1-Methyl-3-n-propyl 2-pyrazolin-5-one (0.2 g, 1.4 mmol) and4-chloroquinoline N-oxide (1.4 mmol) were stirred in acetic anhydride (2mL) at ambient temperature for 2-3 hours. The reaction mixture wasconcentrated and carried out to the next step without furtherpurification. The resulting(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-1-methyl-3-propyl-1H-pyrazol-5(4H)-one(0.71 mmol) was dissolved in ethanol (0.5 mL) and 4-acetamidothiophenol(0.13 g, 0.78 mmol) was added. The reaction mixture was heated to 180°C. using a microwave reactor for 5-10 minutes. The mixture was thenconcentrated and purified by LC-MS to give Example 56. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.67 (t, J=7.45 Hz, 3H) 1.23-1.32 (m, J=7.52, 7.52, 7.52,7.52 Hz, 2H) 2.00 (t, J=7.58 Hz, 2H) 2.09 (s, 3H) 3.29 (s, 3H) 6.53 (s,1H) 7.52-7.57 (m, 1H) 7.67-7.76 (m, 3H) 7.80-7.90 (m, 3H) 8.06 (d,J=8.08 Hz, 1H) 10.34 (s, 1H); ESI-MS: m/z calc'd for C₂₄H₂₄N₄O₂S 432.54.found 433.3 (M+H)⁺.

Example 57(Z)—N-(3-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)phenyl)methanesulfonamide

The tile compound was synthesized from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and3-(methylsulfonamido)phenylboronic acid using Suzuki couplingconditions. The final compound was purified by LC-MS. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.95 (t, J=7.33 Hz, 3H) 1.71 (td, J=14.53, 6.82 Hz, 2H)2.94 (t, J=7.33 Hz, 2H) 3.09 (s, 3H) 7.33 (d, J=7.83 Hz, 1H) 7.41 (d,J=1.77 Hz, 2H) 7.50-7.61 (m, 2H) 7.69 (s, 1H) 7.77-7.83 (m, 2H) 7.99 (d,J=8.34 Hz, 1H) 10.04 (s, 1H); ESI-MS: m/z calc'd for C₂₂H₂₂N₄O₃S 422.5.found 423.3 (M+H)⁺.

Example 58 (Z)-3-amino-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from quinoline N-oxide and methyl2-cyanoacetate under conditions similar to those described in Example 1.¹H NMR (400 MHz, DMSO-D6) δ ppm 5.24 (bs, 2H), 7.43-7.54 (m, 1H) 7.71(t, J=7.33 Hz, 2H) 7.89 (d, J=7.83 Hz, 2H) 8.30 (d, J=8.34 Hz, 1H) 11.14(s, 1H) 11.88 (s, 1H); ESI-MS: m/z calc'd for C₁₂H₁₀N₄O 226.09. found227.2 (M+H)⁺.

Example 59((Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide

The title compound was prepared from (Z)-tert-butyl4-(4-aminophenylthio)-2-(1-(tert-butoxycarbonyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)quinoline-1(2H)-carboxylate and methanesulfonyl chloride according to the proceduredescribed in Example 21. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3H)3.09 (s, 3H) 6.69 (s, 1H) 7.44 (d, J=8.59 Hz, 2H) 7.63 (t, J=7.58 Hz,1H) 7.72 (d, J=8.59 Hz, 2H) 7.83-7.94 (m, 2H) 8.13 (d, J=8.34 Hz, 1H)10.40 (s, 1H); ESI-MS: m/z calc'd for C₂₀H₁₈N₄O₃S₂ 426.08. found 427.3(M+H)⁺.

Example 60 (Z)-3-benzyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

A mixture of 3-benzyl-1H-pyrazol-5(4H)-one (0.234 g, 1.34 mmol) andquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride(1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixturewas concentrated and the resulting solid filtered off and washed with aminimum amount of ether to yield the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H) 7.23-7.29 (m, 6H) 7.61 (t,J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m,2H); ESI-MS: m/z calc'd for C₁₉H₁₅N3O 301.12. found 302.2 (M+H)⁺.

Example 61(Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from 3-benzyl-1H-pyrazol-5(4H)-one and4-chloroquinoline N-oxide under conditions similar to those described inExample 60. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H)7.23-7.32 (m, 5H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d,J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C₁₉H₁₄ClN₃O335.08. found 336.2 (M+H)⁺.

Example 62(Z)-3-benzyl-4-(4-phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one andthiophenol under conditions similar to those described in Example 6. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.76 (s, 2H) 3.98 (bs, 1H) 7.23-7.50 (m,10H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H)8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C₂₅H₁₉9N₃OS 409.12. found410.2 (M+H)⁺.

Example 63(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one and4-aminothiophenol under conditions similar to those described in Example6. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.81 (s, 2H) 6.77-6.79 (m, 3H)7.23-7.30 (m, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.40-7.48 (m, 2H) 7.64 (t,J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.14 (d,J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C₂₅H₂₀N₄OS 424.14. found 424.2(M+H)⁺.

Example 64(Z)—N-(4-(2-(3-benzyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and4-actamidothiophenol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.94 (s, 2H) 2.11 (s, 3H)6.77 (s, 1H) 7.23-7.32 (m, 3H) 7.42-7.50 (m, 2H) 7.65-7.69 (m, 3H)7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35(s, 1H); ESI-MS: m/z calc'd for C₂₇H₂₂N₄O₂S 466.15. found 467.4 (M+H)⁺.

Example 65(Z)-4-(4-(2-methoxyphenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and2-methoxythiophenol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 3.68 (s, 3H)6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H)8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'dfor C₂₀H₁₇N₃O₂S 363.10. found 364.3 (M+H)⁺.

Example 66(Z)-3-methyl-4-(4-(m-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and3-methylbenzenethiol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H) 2.36 (s, 3H)6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.86-7.96 (m, 3H) 7.99 (d, J=8.08 Hz, 1H)8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H); ESI-MS: m/z calc'dfor C₂₀H₁₇N₃OS 347.11. found 348.2 (M+H)⁺.

Example 67 (Z)-methyl3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one andmethyl 3-mercaptobenzoate using a procedure analogous to the onedescribed in Example 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H)3.90 (s, 3 H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.86-7.96 (m, 3H) 7.99 (d,J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H) 13.04 (bs, 1H);ESI-MS: m/z calc'd for C₂₁H₁₇N₃O₃S 391.10. found 392.3 (M+H)⁺.

Example 68 (Z)-methyl2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one andmethyl 2-mercaptobenzoate using a procedure analogous to the onedescribed in Example 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.96 (s, 3H)3.88 (s, 3H) 6.77 (s, 1H) 7.50-7.72 (m, 3H) 7.76-7.92 (m, 3H) 7.96 (d,J=8.12 Hz, 1H) 8.16 (d, J=8.18 Hz, 1H) 10.39 (s, 1H) 13.20 (bs, 1H);ESI-MS: m/z calc'd for C₂₁H₁₇N₃O₃S 391.10. found 392.3 (M+H)⁺.

Example 69(Z)-3-methyl-4-(4-(o-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and2-methylbenzenethiol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.32 (s, 3H)6.79 (s, 1H) 7.58-7.68 (m, 3H) 7.76-7.88 (m, 3H) 7.92 (d, J=8.14 Hz, 1H)8.18 (d, J=8.24 Hz, 1H) 10.38 (s, 1H) 13.10 (bs, 1H); ESI-MS: m/z calc'dfor C₂₀H₁₇N₃OS 347.11. found 348.3 (M+H)⁺.

Example 70 (Z)-methyl3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoicAcid

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one andmethyl 3-mercaptobenzoic acid using a procedure analogous to the onedescribed in Example 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.93 (s, 3H)6.79 (s, 1H) 7.62-7.73 (m, 3H) 7.76-7.88 (m, 3H) 7.94 (d, J=8.18 Hz, 1H)8.12 (d, J=8.26 Hz, 1H) 10.30 (s, 1H) 13.11 (bs, 1H); ESI-MS: m/z calc'dfor C₂₀H₁₅N₃O₃S 377.08. found 378.2 (M+H)⁺.

Example 71(Z)-3-methyl-4-(4-(4-nitrophenyl)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and4-nitrobenzenethiol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.99 (s, 3H) 6.65 (s, 1H)7.03-7.10 (m, 2H) 7.44 (d, J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88(t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.08 (d, J=8.08 Hz, 2H) 13.12(bs, 1H); ESI-MS: m/z calc'd for C₁₉H₁₄N₄O₃S 378.08. found 379.2 (M+H)⁺.

Example 72(Z)-4-(4-(2-hydroxyphenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one

The title compound was prepared from(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and2-mercaptophenol using a procedure analogous to the one described inExample 6. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.08 (s, 3H) 7.08 (s, 1H)7.38-7.68 (m, 3H) 7.76-7.88 (m, 3H) 7.92 (d, J=8.14 Hz, 1H) 8.18 (d,J=8.24 Hz, 1H) 10.38 (s, 1H) 13.10 (bs, 1H); ESI-MS: m/z calc'd forC₁₉H₁₅N₃O₂S 349.09. found 350.3 (M+H)⁺.

4. Biological Testing

The activity of compounds as protein kinase inhibitors may be assayed invitro, in vivo or in a cell line. In vitro assays include assays thatdetermine inhibition of either the phosphorylation activity or ATPaseactivity of the activated protein kinase. Alternate in vitro assaysquantitate the ability of the inhibitor to bind to the protein kinase.Inhibitor binding may be measured by radiolabelling the inhibitor priorto binding, isolating the inhibitor/protein kinase complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with the protein kinase bound to knownradioligands.

A. Determination of Inhibition of AIK

The inhibitory properties of compounds relative to AIK may be determinedby the Direct Fluorescence Polarization detection method (FP) using aGreiner small volume black 384-well-plate format under the followingreaction conditions: 50 mM Hepes pH 7.3, 10 mM MgCl₂, 10 mM NaCl, 1 mMDTT, 0.01% Brij35, 100 nM Fluorescein-LRRASLG peptide (provided bySYNPEP), 5% DMSO, 2.5 uM ATP. Detection of the reaction product isperformed by addition of IMAP binding reagent (Molecular Devices).Reaction product may be determined quantitatively by FP using an AnalystHT plate reader (Molecular Devices) with an excitation wavelength at 485nm and emission at 530 nm and using a Fluorescein 505 dichroic mirror.

The assay reaction may be initiated as follows: 2 μL of (3×) 300 nMFl-Peptide/7.5 uM ATP was added to each well of the plate, followed bythe addition of 2 μL of (3×) inhibitor (2.5 fold serial dilutions for 11data points for each inhibitor) containing 15% DMSO. 2 μL of (3×) 7.5 nMAIK solution may be added to initiate the reaction (final enzymeconcentration was 2.5 nM for AIK). The reaction mixture may then beincubated at room temperature for 45 min, and quenched and developed byaddition of 20 μL of 1 to 400 diluted IMAP binding reagent in 1×proprietary IMAP binding buffer. Fluorescence polarization readings ofthe resulting reaction mixtures may be measured after a 60-minuteincubation at room temperature.

IC50 values may be calculated by non-linear curve fitting of thecompound concentrations and fluorescent polarization values to thestandard IC50 equation. As a reference point for this assay,Staurosporin showed an IC50 of <10 nM.

B. Determination of Inhibition of c-KIT

The inhibitory properties of compounds relative to c-Kit may bedetermined by the Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) method using a small volume black 384-well-plate (Greiner)format under the following reaction conditions: 50 mM Hepes pH 7.3, 10mM MgCl2, 10 mM NaCl, 1 mM DTT, 0.01% Brij35, 250 nMBiotin-EGPWLEEEEEAYGWMDF peptide (provided by SYNPEP), 5% DMSO, 100 uMATP. Detection of the reaction product may be performed by addition ofStreptavidin-APC (Prozyme) and Eu-Anti-phosphotyrosine antibody (PerkinElmer). Reaction product may be determined quantitatively by TR-FRETreading using an Analyst HT plate reader (Molecular Devices) with anexcitation wavelength at 330 nm and emission at 615 nm (Europium)compared to 330 nm excitation (Europium) and emission 665 nm (APC) andusing an Europium 400 dichroic mirror.

The assay reaction may be initiated as follows: 4 μL of (2.5×) 625 nMBiotin-Peptide/250 uM ATP was added to each well of the plate, followedby the addition of 2 μL of (5×) inhibitor (2.5 fold serial dilutions for11 data points for each inhibitor) containing 25% DMSO. 4 μL of (2.5×)c-Kit solution may be added to initiate the reaction (final enzymeconcentration was 0.13 nM for c-Kit). The reaction mixture may then beincubated at room temperature for 30 min, and quenched and developed byaddition of 10 μL of (2×) 3.2 nM Eu-Antibody and 25 nM Streptavidin-APCin 50 mM Hepes pH 7.3, 30 mM EDTA, 0.1% Triton X-100 buffer. TR-FRETreadings of the resulting reaction mixtures may be measured after a60-minute incubation at room temperature on the Analyst HT.

IC50 values may be calculated by non-linear curve fitting of thecompound concentrations and ratio metric Eu:APC values to the standardIC50 equation. As a reference point for this assay, Staurosporin showedan IC50 of <5 nM.

The following abbreviations have been used:

-   -   ATP Adenosine Triphophatase    -   BSA Bovin Serum Albumin    -   EDTA Ethylenediaminetetraacetic acid    -   GSK3 Glycogen synthase kinase 3    -   MOPS Morpholinepropanesulfonic acid    -   SPA Scintillation Proximity Assay

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

1. A compound consisting of the formula:

wherein: R₁ is hydrogen; R₂ is hydrogen or (C₁₋₆)alkyl; R₃ is selectedfrom the group consisting of hydrogen, (C₁₋₁₂)alkyl, alkoxy, thio,hydroxy, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,aryl, heteroaryl, heteroaryloxy, aryloxy, amino, carbonyl, imino,sulfonyl, sulfinyl, halo, cyano, nitro, trifluoromethoxy, andaryl(C₁₋₁₂)alkyl, each unsubstituted or substituted, with the provisothat R₃ is not hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, orheteroaryl when Q is CO; Q is selected from the group consisting of COand CS; R₅ and R₆ are each independently selected from the groupconsisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano,thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted, or R₅ and R₆are taken together to form an unsubstituted or substituted ring; and R₇,R₈, R₉, and R₁₀ are each independently selected from the groupconsisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano,thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each unsubstituted or substituted, or R₆ and R₇, R₇ and R₈, R₈and R₉, or R₉ and R₁₀ are taken together to form an unsubstituted orsubstituted ring.
 2. The compound of claim 1 consisting of the formula:

wherein: R₃ is selected from the group consisting of hydrogen,(C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy,amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro, andtrifluoromethoxy, each unsubstituted or substituted, with the provisothat R₃ is not hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, orheteroaryl when Q is CO; R₇, R₈, and R₉ are each independently selectedfrom the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino,nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each unsubstituted or substituted, or R₆ and R₇, R₇ and R₈, or R₈and R₉ are taken together to form an unsubstituted or substituted ring;and R₁₀ is selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and(C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀ are takentogether to form an unsubstituted or substituted ring.
 3. The compoundof claim 1 consisting of the formula:

wherein: R₇, R₈, and R₉ are each independently selected from the groupconsisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano,thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each unsubstituted or substituted, or R₆ and R₇, R₇ and R₈, or R₈and R₉ are taken together to form an unsubstituted or substituted ring;and R₁₀ is selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and(C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀ are takentogether to form an unsubstituted or substituted ring.
 4. The compoundof claim 1 consisting of the formula:

wherein: R₃ is selected from the group consisting of hydrogen,(C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, aryl, heteroaryl, heteroaryloxy, aryloxy,amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro, andtrifluoromethoxy, each unsubstituted or substituted, with the provisothat R₃ is not hetero(C₂₋₁₂)cycloalkyl, hetero(C₄₋₁₂)bicycloaryl, orheteroaryl when Q is CO; R₇, R₈, and R₉ are each independently selectedfrom the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino,nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each unsubstituted or substituted, or R₆ and R₇, R₇ and R₈, or R₈and R₉ are taken together to form an unsubstituted or substituted ring;and R₁₀ is selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, and(C₁₋₁₀)alkyl, each unsubstituted or substituted, or R₉ and R₁₀ are takentogether to form an unsubstituted or substituted ring.
 5. The compoundof claim 1 consisting of the formula:

wherein: R₃ is selected from the group consisting of hydrogen,(C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy,aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro,and trifluoromethoxy, each unsubstituted or substituted; R₆ is selectedfrom the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino,nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted; and R₈ and R₉are each independently selected from the group consisting of hydrogen,halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group,imino group, sulfonyl group and sulfinyl group, each unsubstituted orsubstituted.
 6. The compound of claim 1 consisting of the formula:

wherein: m is 1 or 2 Q₁ is selected from the group consisting of CH₂,CO, S, SO, SO₂, O, and NR₁₃; U₁, V₁, W₁, X₁, Y₁, and Z₁ are eachindependently selected from the group consisting of CR₁₂ and N; R₃ isselected from the group consisting of hydrogen, (C₁₋₁₂)alkyl, alkoxy,thio, hydroxy, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy,(C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy, aryloxy, amino, carbonyl,imino, sulfonyl, sulfinyl, halo, cyano, nitro, and trifluoromethoxy,each unsubstituted or substituted; R₈ and R₉ are each independentlyselected from the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl,amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each unsubstituted or substituted; R₁₁ is selected from the groupconsisting of hydrogen, halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano,thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted, or any twoR₁₁ are taken together to form a substituted or unsubstituted ring; eachR₁₂ is independently selected from the group consisting of hydrogen,halo, halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl,(C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy,aryloxy, heteroaryloxy, carbonyl, imino, sulfonyl, and sulfinyl, eachunsubstituted or substituted; and R₁₃ is selected from the groupconsisting of hydrogen, halo(C₁₋₁₀)alkyl, amino, sulfonamide,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl, sulfinyl, and sulfinyl, each unsubstituted or substituted. 7.The compound of claim 6, wherein Q₁ is CO.
 8. The compound of claim 6,wherein Q₁ is S.
 9. The compound of claim 6, wherein R₁₁ is selectedfrom the group consisting of arylsulfonyl, heteroarylsulfonyl,arylamino, heteroarylamino, arylthio, and heteroarylthio, eachunsubstituted or substituted.
 10. The compound of claim 6, wherein R₁₁is substituted with a substituent selected from the group consisting of

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.
 11. The compound of claim 1 consisting of the formula:

wherein: m is 1 or 2; Q₁ is selected from the group consisting of CH₂,CO, S, SO, SO₂, O, and NR₁₃; R₃ is selected from the group consisting ofhydrogen, (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy,aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro,and trifluoromethoxy, each unsubstituted or substituted; R₈ and R₉ areeach independently selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each unsubstituted or substituted; R₁₁ isselected from the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl,amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted, or any twoR₁₁ are taken together to form a substituted or unsubstituted ring; andR₁₃ is selected from the group consisting of hydrogen, halo(C₁₋₁₀)alkyl,amino, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, sulfonyl, and sulfinyl, eachunsubstituted or substituted.
 12. The compound of claim 11, wherein Q₁is CO.
 13. The compound of claim 11, wherein Q₁ is S.
 14. The compoundof claim 11, wherein R₁₁ is selected from the group consisting ofarylsulfonyl, heteroarylsulfonyl, arylamino, heteroarylamino, arylthio,and heteroarylthio, each unsubstituted or substituted.
 15. The compoundof claim 11, wherein R₁₁ is substituted with a substituent selected fromthe group consisting of

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.
 16. The compound of claim 1 consisting of the formula:

wherein: m is 1 or 2; Q₁ is selected from the group consisting of CH₂,CO, S, SO, SO₂, O, and NR₁₃; R₃ is selected from the group consisting ofhydrogen, (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy,aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro,and trifluoromethoxy, each unsubstituted or substituted; R₈ and R₉ areeach independently selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgrow and sulfinyl group, each unsubstituted or substituted; R₁₁ isselected from the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl,amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted, or any twoR₁₁ are taken together to form a substituted or unsubstituted ring; andR₁₃ is selected from the group consisting of hydrogen, halo(C₁₋₁₀)alkyl,amino, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, sulfonyl, and sulfinyl, eachunsubstituted or substituted.
 17. The compound of claim 16, wherein Q₁is CO.
 18. The compound of claim 16, wherein Q₁ is S.
 19. The compoundof claim 16, wherein R₁₁ is selected from the group consisting ofarylsulfonyl, heteroarylsulfonyl, arylamino, heteroarylamino, arylthio,and heteroarylthio, each unsubstituted or substituted.
 20. The compoundof claim 16, wherein R₁₁ is substituted with a substituent selected fromthe group consisting of

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.
 21. The compound of claim 1 consisting of the formula:

wherein: m is 1 or 2; Q₁ is selected from the group consisting of CH₂,CO, S, SO, SO₂, O, and NR₁₃; R₃ is selected from the group consisting ofhydrogen, (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl, heteroaryloxy,aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl, halo, cyano, nitro,and trifluoromethoxy, each unsubstituted or substituted; R₈ and R₉ areeach independently selected from the group consisting of hydrogen, halo,halo(C₁₋₁₀)alkyl, amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each unsubstituted or substituted; R₁₁ isselected from the group consisting of hydrogen, halo, halo(C₁₋₁₀)alkyl,amino, nitro, cyano, thio, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,imino(C₁₋₃)alkyl, (C₁₋₁₀)alkylamino, amino(C₁₋₁₀)alkyl, aryl,heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, imino,sulfonyl, and sulfinyl, each unsubstituted or substituted, or any twoR₁₁ are taken together to form a substituted or unsubstituted ring; andR₁₃ is selected from the group consisting of hydrogen, halo(C₁₋₁₀)alkyl,amino, sulfonamide, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)alkylamino, amino (C₁₋₁₀)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, sulfonyl, and sulfinyl, eachunsubstituted or substituted.
 22. The compound of claim 21, wherein Q₁is CO.
 23. The compound of claim 21, wherein Q₁ is S.
 24. The compoundof claim 21, wherein R₁₁ is selected from the group consisting ofarylsulfonyl, heteroarylsulfonyl, arylamino, heteroarylamino, arylthio,and heteroarylthio, each unsubstituted or substituted.
 25. The compoundof claim 21, wherein R₁₁ is substituted with a substituent selected fromthe group consisting of

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.
 26. The compound of claim 1, wherein R₅ is selected fromthe group consisting of arylthio, heteroarylthio, (C₁₋₁₀)alkylthio,sulfonylaryl and sulfonylheteroaryl, each unsubstituted or substituted.27. The compound of claim 1, wherein R₆ is selected from the groupconsisting of hydrogen, halo, alkoxy and thio, each unsubstituted orsubstituted.
 28. The compound of claim 1, wherein R₆ is selected fromthe group consisting of arylthio, heteroarylthio, (C₁₋₁₀)alkylthio,sulfonylaryl and sulfonylheteroaryl, each unsubstituted or substituted.29. The compound of claim 1, wherein R₆ is selected from the groupconsisting of arylsulfonyl, heteroarylsulfonyl, arylamino,heteroarylamino, arylthio, and heteroarylthio, each unsubstituted orsubstituted.
 30. The compound of claim 1, wherein R₆ is selected fromthe group consisting of arylsulfonyl, heteroarylsulfonyl, arylamino,heteroarylamino, arylthio, and heteroarylthio, each substituted with asubstituent selected from the group consisting of:

wherein R₁₄ is selected from the group consisting of (C₁₋₆)alkyl,amino(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, alkylthio(C₁₋₆)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl, heteroaryl, andalkyloxyalkoxy.
 31. The compound of claim 1, wherein R₆ is anunsubstituted or substituted phenylthio.
 32. The compound of claim 1,wherein R₆ is a carboxamidophenylthio.
 33. The compound of claim 1,wherein R₈ is selected from the group consisting of hydrogen, halo,alkoxy and thio, each unsubstituted or substituted.
 34. The compound ofclaim 1, wherein R₈ is selected from the group consisting of hydrogen;—O—(C₁₋₆)alkylamino; hydroxy; halo; trifluoromethyl; cyano; mercapto;nitro; amino; carboxy; carbamoyl; formyl; sulphamoyl; (C₁₋₆)alkyl;(C₁₋₆)alkoxy; —(C₁₋₆)alkyl-S(O)_(n), wherein n is 0, 1 or 2;—(C₁₋₆)alkylamino; —(C₁₋₆)dialkylamino; —(C₁₋₆)alkoxycarbonyl;—(C₁₋₆)alkylcarbamoyl; —(C₁₋₆)dialkylcarbamoyl; —(C₂₋₆)alkanoyl;—(C₁₋₆)alkanoyloxy; —(C₁₋₆)alkanoylamino; —(C₁₋₆)alkylsulphamoyl;—(C₁₋₆)dialkylsulphamoyl; —(C₁₋₆)alkylsulphonylamino;—(C₁₋₆)alkylsulphonyl-(C₁₋₆)alkyl-amino, each unsubstituted orsubstituted.
 35. The compound of claim 1, wherein at least one of R₈ andR₉ is —B—(CH₂)_(p)—A, wherein: A is selected from the group consistingof halo; hydroxy; (C₁₋₆)alkoxy; (C₁₋₆)alkyl-S(O)_(n) wherein n is 0, 1or 2; cyano; amino; (C₁₋₆)alkylamino; (C₁₋₆)dialkylamino; carboxy;(C₁₋₆)alkoxycarbonyl; carbamoyl; (C₁₋₆)alkylcarbamoyl; and(C₁₋₆)dialkylcarbamoyl, each unsubstituted or substituted; p is 0-6; andB is selected from the group consisting of a bond; oxa; imino; thia;(C₁₋₆)alkylamino; and —C(O)NH—, each unsubstituted or substituted. 36.The compound of claim 1, wherein at least one of R₈ and R₉ is —E—D,wherein: D is selected from the group consisting of aryl, heteroaryl orheterocyclyl, each unsubstituted or substituted; and E is selected fromthe group consisting of a bond; (C₁₋₆)alkylene; (C₁₋₆)alkyleneoxy; oxy;imino; (C₁₋₆)alkylamino; (C₁₋₆)alkyleneimino;(C₁₋₆)alkyl-(C₁₋₆)alkyleneimino; (C₁₋₆)alkyleneoxy-(C₁₋₆)alkylene;(C₁₋₆)alkyleneimino-(C₁₋₆)alkylene;(C₁₋₆)alkyl-(C₁₋₆)alkyleneimino-(C₁₋₆)alkylene; —C(O)NH—; —SO₂—NH—;—NH—SO₂—; or (C₂₋₆)alkanoylimino, each unsubstituted or substituted. 37.The compound of claim 1, wherein R₈ is hydrogen.
 38. The compound ofclaim 1, wherein R₉ is hydrogen.
 39. The compound of claim 1, wherein R₂is hydrogen.
 40. The compound of claim 1, wherein R₃ is selected fromthe group consisting of hydrogen, (C₁₋₁₂)alkyl, alkoxy, thio, hydroxy,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkoxy, (C₉₋₁₂)bicycloaryl, aryl,heteroaryloxy, aryloxy, amino, carbonyl, imino, sulfonyl, sulfinyl,halo, cyano, nitro, and trifluoromethoxy, each unsubstituted orsubstituted.
 41. The compound of claim 1, wherein R₃ is selected fromthe group consisting of methyl, ethyl, propyl, cyclopropyl, andisopropyl.
 42. The compound of claim 1, wherein Q is CO.
 43. Thecompound of claim 1, wherein Q is CS.
 44. A compound selected from thegroup consisting of:(Z)-3-methyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-4-(4-(6-aminopyridin-3-ylamino)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-4-(4-ethoxyquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-3-methyl-4-(4-(phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-6-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)nicotinicacid;(Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-ethyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-ethyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;(Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-3-methyl-4-(4-(pyridin-2-ylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;(Z)—N-(4-(2-(3-isopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide;(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)ethanesulfonamide;(Z)-2-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)benzamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclobutanecarboxamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopentanecarboxamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)furan-2-carboxamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)thiophene-2-carboxamide;(Z)-2-methoxy-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propionamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butyramide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;(Z)-2-methoxyethyl4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenylcarbamate;(Z)-3-(methylthio)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide;(Z)-4-(dimethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)butanamide;(Z)-3-(diethylamino)-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)propanamide;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)isobutyramide;(R,Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)pyrrolidine-2-carboxamide;(Z)-1-methyl-N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)piperidine-4-carboxamide;(Z)—N-(4-(6-methoxy-2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(4-aminophenylthio)-6-methoxyquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-cyclopropyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-6-methoxy-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)—N-(4-(2-(3-cyclohexyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylsulfonyl)phenyl)propionamide;(Z)-5-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylamino)-1H-indazol-3(2H)-one;(Z)—N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)methanesulfonamide;(Z)-3-phenyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)—N-methyl-4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzenesulfonamide;(Z)-3-cyclopropyl-4-(isoquinolin-1(2H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(1-methyl-5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)—N-(3-(2-(5-oxo-3-propyl-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)phenyl)methanesulfonamide;(Z)-3-amino-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;((Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)methanesulfonamide;(Z)-3-benzyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-3-benzyl-4-(4-phenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)—N-(4-(2-(3-benzyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)acetamide;(Z)-4-(4-(2-methoxyphenylthio)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-3-methyl-4-(4-(m-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-methyl3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate;(Z)-methyl2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoate;(Z)-3-methyl-4-(4-(o-tolylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-methyl3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzoicacid;(Z)-3-methyl-4-(4-(4-nitrophenyl)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(4-(2-hydroxyphenylthio)quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;3-cyclopropyl-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one;3-((Z)-5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acrylamide;3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)propanamide;2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)cyclopropanecarboxamide;N-methyl-2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)cyclopropane-1-sulfonamide;3-(4-aminobenzyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;3-(4-aminophenylamino)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;3-(4-aminophenylthio)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;N-(4-((5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)methyl)phenyl)acetamide;N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-ylamino)phenyl)acetamide;N-(4-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-ylthio)phenyl)acetamide;3-amino-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)acetamide;1-methyl-3-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)urea;1-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)-3-phenylurea;2-(4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide;2-(4-(6-(2-(diethylamino)ethoxy)quinolin-2(1H)-ylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-N-methylcyclopropane-1-sulfonamide;N-methyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)benzenesulfonamide;(Z)-3-(2-(ethylsulfonyl)cyclopropyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-4-(6-(2-(dimethylamino)ethoxy)quinolin-2(1H)-ylidene)-3-(2-(ethylsulfonyl)cyclopropyl)-1H-pyrazol-5(4H)-one;(Z)—N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzamide;(Z)-3-(ethylsulfonyl)-N-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)benzamide;(Z)-4-(4-(3-(ethylsulfonyl)phenyl)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-4-(4-(1-(ethylsulfonyl)-1H-indol-4-yl)quinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one;(Z)-2-((3-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)-1H-pyrazol-1-yl)methyl)benzonitrile;(Z)-2-((4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile;(Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-4-yl)methyl)benzonitrile;(Z)-2-((2-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-5-yl)methyl)benzonitrile;(Z)-2-((5-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)thiazol-2-yl)methyl)benzonitrile;(Z)—N-(4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinoline-4-carbonyl)phenyl)cyclopropanecarboxamide;(Z)—N-(4-((2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-yl)methyl)phenyl)cyclopropanecarboxamide;(Z)—N-(2-ethyl-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;(Z)—N-(2-methoxy-4-(2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,2-dihydroquinolin-4-ylthio)phenyl)cyclopropanecarboxamide;(Z)-3-(4-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-3-(3-(ethylsulfonyl)phenyl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)-3-(1-(ethylsulfonyl)-1H-indol-5-yl)-4-(quinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one;(Z)—N-cyclopropyl-2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)thiazole-5-carboxamide;and(Z)—N-(2-(5-oxo-4-(quinolin-2(1H)-ylidene)-4,5-dihydro-1H-pyrazol-3-yl)thiazol-5-yl)cyclopropanecarboxamide.45. The compound of claim 1, wherein the compound is in the form of apharmaceutically acceptable salt thereof.
 46. The compound of claim 1,wherein the compound is present in a mixture of stereoisomers.
 47. Thecompound of claim 1, wherein the compound comprises a singlestereoisomer.